A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia: Implications of Physical Activity to Tumor Regression

*Gabriel Cardial Tobias, João Lucas Penteado Gomes, Ursula Paula Renó Soci, Tiago Fernandes and Edilamar Menezes de Oliveira*

## **Abstract**

In the last decades, there has been a remarkable advance in the treatment of most types of cancer, improving the patient's prognosis. During cancer progression, tumor cells develop several biological changes to support initiation, proliferation, and resistance to death. Nearly 50–80% of all oncologic patients experience rapid weight loss that is related to ~20% of cancer-related deaths. Cancer cachexia is a syndrome characterized by loss of skeletal muscle mass, anorexia, and anemia. A lot of effort in scientific investigation has contributed to the understanding of cancer processes, in which epigenetic changes, as microRNAs, can influence cancer progression. Therefore, useful strategies to control the cancer-induced epigenetic changes in the tumor cells can have a key role in a clinical perspective to decrease the cancer development and aggressiveness. Physical activity has been proposed as a suitable tool to manage tumor growth and cachexia and to improve the deleterious sequelae experienced during cancer treatment. Although the molecular mechanisms involved in these responses are poorly understood, this chapter aims to discuss the role of microRNAs in the cancer-induced epigenetic changes and how physical activity could influence the epigenetic control of tumor cells and cachexia and their potential role in clinical applications for cancer.

**Keywords:** epigenetic, cancer, hallmarks of cancer, cachexia, physical activity, tumor progression, microRNAs

## **1. Introduction: hallmarks of cancer, genetics and epigenetics**

In the last decades, there has been a remarkable advance in the treatment of most types of cancer, improving the patient's prognosis [1]. However, cancer remains the second major cause of death in the world and major cause of death in the rich countries [2, 3]. Cancer consists in a set of diseases characterized by the progressive accumulation of mutations in the cell. These mutations provide changes in

the intracellular environment that induce advantages for its proliferation as well as greater resistance to mechanisms of cell death. A dysfunctional cluster of these cells is classically known as tumor. Currently, cancer is understood as a microenvironment, in which the interactions between the cellular elements that compose it are determinants for the progression of the disease. For example, such elements would be involved in the interaction of tumor cells with normal cells such as fibroblasts, adipocytes, immune system cells, and endothelial cells [4–6]. All these cellular interactions support the development of cancer cachexia, which affects approximately 50–80% of cancer patients, and more than 25% of cancer deaths are a direct consequence of cachexia [7]. Cancer cachexia is directly related to a reduction in tolerance to physical effort [8], a reduction in tolerance to cancer treatments [9], and a shorter patient survival [10].

During cancer progression, tumor cells develop a number of important biological changes to support initiation, proliferation, and resistance to death known as cancer hallmarks [5, 6]. Hanahan and Weinberg [5, 6] discuss 10 biological capabilities acquired by tumor cells that may be common among the different neoplasms and are important for the development and growth of the tumor mass, namely: (1) sustaining proliferative signaling, (2) loss of growth suppressors, (3) resisting cell death, (4) enabling replicative immortality, (5) inducing angiogenesis, (6) activating invasion and metastasis, (7) genome instability, (8) inflammation, (9) reprogramming of energy metabolism, and (10) loss of immune destruction [5, 6]. Among the 10 cancer-related biological processes, we point out that 6 are of fundamental importance for tumor mass growth.

## 1.Sustaining proliferative signaling

In normal tissues, there is a careful control of the release of growth and proliferation factors for the regulation of the cell cycle, which ensures adequate tissue architecture and function. However, tumor cells show abnormal proliferation signaling, which promote exacerbated cell proliferation that generates morphological and functional tissue disarrangement. Some mutations are shown as probable causes of a normal cell to initiate a sustained proliferation and tumorigenesis. For example, mutation of *PIK3CA* gene and tyrosine kinases are mutations well described that promote sustained proliferation of a tumor cell [11].

### 2.Loss of growth suppressors.

Tumor cells bypass growth suppressor signals through the escape of mechanisms that negatively control cell proliferation. Usually, tumor cells show loss of *p53*, a well-known tumor suppressor that controls proliferation, senescence, and cellular apoptotic programs, culminating in the uncontrolled growth of tumor cells. Tumor cells must also bypass powerful programs that negatively regulate cell proliferation; many of these programs depend on the actions of tumor suppressor genes [12].

## 3.Resisting cell death.

Over the past few decades, the literature has shown that apoptosisprogrammed cell death serves as a natural barrier to the development of cancer. Apoptosis is triggered in response to various physiological stresses that tumor cells undergo during the course of tumorigenesis or as a result of antineoplastic therapies. However, tumor cells have the ability to resist apoptosis and subsequently progress to conditions of malignancy and resistance to therapy [5].

**23**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

In healthy tissues, most normal cells have growth and cell division capacity controlled, but tumor cells have unlimited replicative potential, which favors

In any tissue, the presence of vessels allows both the uptake of nutrients and oxygen and the release of substances not useful for the cells. Moreover, angiogenesis occurs temporarily in response to some stimulation such as healing and the female reproductive cycle, being a transient process. However, this process is sustained and dysfunctional, since new vessels that present less coverage of

Tissue invasion and metastasis are probably the most relevant features developed by tumor cells, since the major cause of cancer death is associated with the formation of metastatic tumors. Metastasis is the formation of a new tumor, originating from the primary tumor. This is a complex process in which primary tumor cells invade blood and lymphatic circulation, spreading and

To reach the circulation and invade distant tissues, tumor cells need to modify their configuration and undergo a process named epithelial-mesenchymal transition (EMT). Thus, tumor cells with epithelial characteristics deactivate the mechanisms of cell adhesion and acquire locomotor properties, becoming able to infiltrate the stroma and have access to blood and lymphatic vessels [14, 15]. Moreover, for the colonization of tumor cells in distant tissues, the preparation of the "*premetastatic niche,*" which corresponds to the preparation of the metastatic tissue target of the tumor cells, is fundamental. The process of formation of the *premetastatic niche* involves an intricate cellular signaling at the systemic and local level, involving tumor-secreted factors and tumor-shed extracellular vesicle interaction [16]. Additionally, although Hanahan and Weinberg [5, 6] demonstrate possible treatments against hallmarks of cancer, the individual response to various treatments is still unpredictable [17, 18], demonstrating the plasticity of tumor cells [19–23]. The understanding of *premetastatic niche* is a new paradigm for the initiation of metastasis that can enable the clinical body to fight metastasis, and would benefit greatly from understanding the pathological processes

Cancer is considered a typically genetic disease; however, epigenetic modifications

play an important role in the development and progression of cancer [5, 6, 25–27]. The term "epigenetics" was originally described by Conrad Waddington to describe hereditary changes in a cell phenotype that were independent of changes in

Epigenetic modifications reflect a complexity of factors that determine the condensation state of chromatin, which determines whether the DNA is accessible to proteins that control gene transcription. A relaxed or "open" chromatin state allows gene transcription, while a condensed or "closed" chromatin condition prevents gene transcription [25, 26, 28–31]. Epigenetic mechanisms currently believed to play a role in the development of cancer include: (1) DNA methylation of cytosine bases

pericytes appear continuously, favoring tumor growth [5].

forming colonies at distant sites from the primary tumor [13].

occurring before the development of macrometastases [24].

**2. Epigenetics and cancer**

DNA sequence [28].

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

4.Enabling replicative immortality.

the development of tumors [5].

6.Activating invasion and metastasis.

5.Inducing angiogenesis.

## 4.Enabling replicative immortality.

In healthy tissues, most normal cells have growth and cell division capacity controlled, but tumor cells have unlimited replicative potential, which favors the development of tumors [5].

5.Inducing angiogenesis.

*Epigenetics*

and a shorter patient survival [10].

fundamental importance for tumor mass growth.

1.Sustaining proliferative signaling

tumor cell [11].

2.Loss of growth suppressors.

tumor suppressor genes [12].

resistance to therapy [5].

3.Resisting cell death.

the intracellular environment that induce advantages for its proliferation as well as greater resistance to mechanisms of cell death. A dysfunctional cluster of these cells is classically known as tumor. Currently, cancer is understood as a microenvironment, in which the interactions between the cellular elements that compose it are determinants for the progression of the disease. For example, such elements would be involved in the interaction of tumor cells with normal cells such as fibroblasts, adipocytes, immune system cells, and endothelial cells [4–6]. All these cellular interactions support the development of cancer cachexia, which affects approximately 50–80% of cancer patients, and more than 25% of cancer deaths are a direct consequence of cachexia [7]. Cancer cachexia is directly related to a reduction in tolerance to physical effort [8], a reduction in tolerance to cancer treatments [9],

During cancer progression, tumor cells develop a number of important biologi-

In normal tissues, there is a careful control of the release of growth and proliferation factors for the regulation of the cell cycle, which ensures adequate tissue architecture and function. However, tumor cells show abnormal proliferation signaling, which promote exacerbated cell proliferation that generates morphological and functional tissue disarrangement. Some mutations are shown as probable causes of a normal cell to initiate a sustained proliferation and tumorigenesis. For example, mutation of *PIK3CA* gene and tyrosine kinases are mutations well described that promote sustained proliferation of a

Tumor cells bypass growth suppressor signals through the escape of mechanisms that negatively control cell proliferation. Usually, tumor cells show loss of *p53*, a well-known tumor suppressor that controls proliferation, senescence, and cellular apoptotic programs, culminating in the uncontrolled growth of tumor cells. Tumor cells must also bypass powerful programs that negatively regulate cell proliferation; many of these programs depend on the actions of

Over the past few decades, the literature has shown that apoptosisprogrammed cell death serves as a natural barrier to the development of cancer. Apoptosis is triggered in response to various physiological stresses that tumor cells undergo during the course of tumorigenesis or as a result of antineoplastic therapies. However, tumor cells have the ability to resist apoptosis and subsequently progress to conditions of malignancy and

cal changes to support initiation, proliferation, and resistance to death known as cancer hallmarks [5, 6]. Hanahan and Weinberg [5, 6] discuss 10 biological capabilities acquired by tumor cells that may be common among the different neoplasms and are important for the development and growth of the tumor mass, namely: (1) sustaining proliferative signaling, (2) loss of growth suppressors, (3) resisting cell death, (4) enabling replicative immortality, (5) inducing angiogenesis, (6) activating invasion and metastasis, (7) genome instability, (8) inflammation, (9) reprogramming of energy metabolism, and (10) loss of immune destruction [5, 6]. Among the 10 cancer-related biological processes, we point out that 6 are of

**22**

In any tissue, the presence of vessels allows both the uptake of nutrients and oxygen and the release of substances not useful for the cells. Moreover, angiogenesis occurs temporarily in response to some stimulation such as healing and the female reproductive cycle, being a transient process. However, this process is sustained and dysfunctional, since new vessels that present less coverage of pericytes appear continuously, favoring tumor growth [5].

## 6.Activating invasion and metastasis.

Tissue invasion and metastasis are probably the most relevant features developed by tumor cells, since the major cause of cancer death is associated with the formation of metastatic tumors. Metastasis is the formation of a new tumor, originating from the primary tumor. This is a complex process in which primary tumor cells invade blood and lymphatic circulation, spreading and forming colonies at distant sites from the primary tumor [13].

To reach the circulation and invade distant tissues, tumor cells need to modify their configuration and undergo a process named epithelial-mesenchymal transition (EMT). Thus, tumor cells with epithelial characteristics deactivate the mechanisms of cell adhesion and acquire locomotor properties, becoming able to infiltrate the stroma and have access to blood and lymphatic vessels [14, 15]. Moreover, for the colonization of tumor cells in distant tissues, the preparation of the "*premetastatic niche,*" which corresponds to the preparation of the metastatic tissue target of the tumor cells, is fundamental. The process of formation of the *premetastatic niche* involves an intricate cellular signaling at the systemic and local level, involving tumor-secreted factors and tumor-shed extracellular vesicle interaction [16]. Additionally, although Hanahan and Weinberg [5, 6] demonstrate possible treatments against hallmarks of cancer, the individual response to various treatments is still unpredictable [17, 18], demonstrating the plasticity of tumor cells [19–23]. The understanding of *premetastatic niche* is a new paradigm for the initiation of metastasis that can enable the clinical body to fight metastasis, and would benefit greatly from understanding the pathological processes occurring before the development of macrometastases [24].

## **2. Epigenetics and cancer**

Cancer is considered a typically genetic disease; however, epigenetic modifications play an important role in the development and progression of cancer [5, 6, 25–27].

The term "epigenetics" was originally described by Conrad Waddington to describe hereditary changes in a cell phenotype that were independent of changes in DNA sequence [28].

Epigenetic modifications reflect a complexity of factors that determine the condensation state of chromatin, which determines whether the DNA is accessible to proteins that control gene transcription. A relaxed or "open" chromatin state allows gene transcription, while a condensed or "closed" chromatin condition prevents gene transcription [25, 26, 28–31]. Epigenetic mechanisms currently believed to play a role in the development of cancer include: (1) DNA methylation of cytosine bases

in CG-rich sequences, called CpG islands; (2) posttranslational modification of histones (proteins that form the nucleosomes), which regulate the packaging structure of DNA (called chromatin); and (3) microRNAs (miRs) and noncoding RNAs [25, 26, 28–31].

Although DNA methylation and histone modifications are important components of epigenetic regulation [25, 26, 28–31], here we will focus on the role of alterations in miRs expression, since their expression is regulated through various mechanisms, including epigenetic modifications, and because their functions are aberrant in cancer, boosting the progression of the disease.

## **3. MicroRNAs**

MiRs are a class of molecules that have an important role in the regulation of protein expression, even after the transcription of messenger RNA (mRNA).

MiRs are characterized as small RNAs of approximately 17–22 nucleotides, noncoding proteins, that act by binding to the mRNA, repressing the translation of proteins. MiRs are found in several organisms as animals and plants and control a lot of physiological and pathological processes. Evidence shows that at least onethird of all biological processes are controlled by miRs [32].

This class of molecules was first observed in 1993 by Lee et al., which demonstrated that miR *lin-4* was associated with larval development of *C elegans* [33]. Although the discovery of the first miR occurred in 1993, miRs researches only progressed in the year 2000, when miR *lin-4* was found to participate in the posttranscriptional control of *lin-14* protein through the complementary binding of miR with the 3' untranslated region (3'UTR region) of the protein mRNA [34]. After the pioneering study by Hong et al., many studies have been developed to demonstrate that small RNAs could participate in posttranscriptional controls. Thus, Ambros observed that miR *let-7* had a partially complementary binding to the 3'UTR region of the *lin-4* protein mRNA, negatively controlling its protein expression [34, 35]. These findings led to the discovery of new miRs, and more than 30,000 mature miRs are now known in the most diverse organisms [32].

As mentioned, miRs exert their action through partially or totally binding to the 3'UTR region of the target mRNA. The complete complementarity induces the degradation of the mRNAs, being commonly observed in plants. In mammals, there is partial complementarity, which inhibits the translation of the target transcript [36].

The miRs bind their *seed* region, that in mammals comprises 2–8 nucleotide, with the target mRNA, present in the 3'UTR region, where only some of the base pairs are complementary. Due to the imperfect pairing and small size of these molecules, there is the possibility of an miR presenting various targets [36].

The biogenesis of miRs begins with the action of the enzyme RNA polymerase II that generates a primary transcript called pri-miR. The pri-miR has a hairpin double helix structure with approximately 300 nucleotides. Still in the cell nucleus, the Drosha enzyme and its cofactor DGCR8 cleave the pri-miR, forming its precursor, the pre-miR. The pre-miR is exported to the cytosol by the exportin 5 enzyme. In the cytoplasm, the pre-miR is cleaved by the enzyme dicer, originating two strands together, one being the mature miR and the other called an antisense. Dicer cleaves again and separates the duplex. The mature miR is then incorporated by a multimeric complex named RISC that contains argonaute protein (AGO) as showed in **Figure 1**, while the other strand can be degraded or incorporated in other RISC complex to exert negative regulation of target mRNAs [32].

**25**

**Figure 1.**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

Recently, the interest in the study of miRs has increased, since they exert a paracrine function and are effective in the tissue communication. Also, an miR can exert the same function on different cell types, as different function in the same cells. In 2008, the presence of miRs in plasma and other biological fluids was discovered, demonstrating that miRs are viable in the extracellular environment and important signaling molecules. There are circulating miRs in almost all biological fluids, including: milk, plasma, serum, saliva, urine, tear, and amniotic fluid [37]. Circulating miRs are remarkably stable, resistant to RNase activity, freeze-thaw cycles as well as extreme pH. This stability is associated with the carriers that carry them and can be secreted by the cells through different vesicles such as exosomes,

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

HDL, or AGO proteins containing apoptotic bodies [37].

*Canonical pathway of biogenesis of miRs [31]. https://smart.servier.com/image-set-download/.*

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia… DOI: http://dx.doi.org/10.5772/intechopen.84847*

Recently, the interest in the study of miRs has increased, since they exert a paracrine function and are effective in the tissue communication. Also, an miR can exert the same function on different cell types, as different function in the same cells. In 2008, the presence of miRs in plasma and other biological fluids was discovered, demonstrating that miRs are viable in the extracellular environment and important signaling molecules. There are circulating miRs in almost all biological fluids, including: milk, plasma, serum, saliva, urine, tear, and amniotic fluid [37]. Circulating miRs are remarkably stable, resistant to RNase activity, freeze-thaw cycles as well as extreme pH. This stability is associated with the carriers that carry them and can be secreted by the cells through different vesicles such as exosomes, HDL, or AGO proteins containing apoptotic bodies [37].

**Figure 1.** *Canonical pathway of biogenesis of miRs [31]. https://smart.servier.com/image-set-download/.*

*Epigenetics*

26, 28–31].

**3. MicroRNAs**

transcript [36].

in CG-rich sequences, called CpG islands; (2) posttranslational modification of histones (proteins that form the nucleosomes), which regulate the packaging structure of DNA (called chromatin); and (3) microRNAs (miRs) and noncoding RNAs [25,

Although DNA methylation and histone modifications are important components of epigenetic regulation [25, 26, 28–31], here we will focus on the role of alterations in miRs expression, since their expression is regulated through various mechanisms, including epigenetic modifications, and because their functions are

MiRs are a class of molecules that have an important role in the regulation of protein expression, even after the transcription of messenger RNA (mRNA). MiRs are characterized as small RNAs of approximately 17–22 nucleotides, noncoding proteins, that act by binding to the mRNA, repressing the translation of proteins. MiRs are found in several organisms as animals and plants and control a lot of physiological and pathological processes. Evidence shows that at least one-

This class of molecules was first observed in 1993 by Lee et al., which demonstrated that miR *lin-4* was associated with larval development of *C elegans* [33]. Although the discovery of the first miR occurred in 1993, miRs researches only progressed in the year 2000, when miR *lin-4* was found to participate in the posttranscriptional control of *lin-14* protein through the complementary binding of miR with the 3' untranslated region (3'UTR region) of the protein mRNA [34]. After the pioneering study by Hong et al., many studies have been developed to demonstrate that small RNAs could participate in posttranscriptional controls. Thus, Ambros observed that miR *let-7* had a partially complementary binding to the 3'UTR region of the *lin-4* protein mRNA, negatively controlling its protein expression [34, 35]. These findings led to the discovery of new miRs, and more than 30,000 mature

As mentioned, miRs exert their action through partially or totally binding to the 3'UTR region of the target mRNA. The complete complementarity induces the degradation of the mRNAs, being commonly observed in plants. In mammals, there is partial complementarity, which inhibits the translation of the target

The miRs bind their *seed* region, that in mammals comprises 2–8 nucleotide, with the target mRNA, present in the 3'UTR region, where only some of the base pairs are complementary. Due to the imperfect pairing and small size of these molecules, there is the possibility of an miR presenting various targets [36].

The biogenesis of miRs begins with the action of the enzyme RNA polymerase II that generates a primary transcript called pri-miR. The pri-miR has a hairpin double helix structure with approximately 300 nucleotides. Still in the cell nucleus,

the Drosha enzyme and its cofactor DGCR8 cleave the pri-miR, forming its precursor, the pre-miR. The pre-miR is exported to the cytosol by the exportin 5 enzyme. In the cytoplasm, the pre-miR is cleaved by the enzyme dicer, originating two strands together, one being the mature miR and the other called an antisense. Dicer cleaves again and separates the duplex. The mature miR is then incorporated by a multimeric complex named RISC that contains argonaute protein (AGO) as showed in **Figure 1**, while the other strand can be degraded or incorporated in

other RISC complex to exert negative regulation of target mRNAs [32].

aberrant in cancer, boosting the progression of the disease.

third of all biological processes are controlled by miRs [32].

miRs are now known in the most diverse organisms [32].

**24**

## **4. microRNAs and cancer**

The miRs play a key role in the control of various physiological and pathological processes. Many studies demonstrate the participation of miRs during the progression of several types of cancer. MiRs present altered expression in tumors, and many studies are being conducted with this new class of molecules to elucidate their role in controlling the pathophysiology of the disease [36, 38, 39].

There is evidence that miRs are also involved in regulation of hallmarks of cancer and thus in the progression of cancer [5, 15]. In view of this, there is an effort by the scientific community to understand the mechanisms involving miRs and the development of cancer aiming to develop cancer-specific gene therapies [40]. The aim of these efforts is to improve responses to conventional drugs for the cancer treatment, specifically suppress oncogenic processes, and improve the prognosis of the disease.

The *miR-124* was one of the first studied miRs involved in the pathogenesis of cancer [41]. *MiR-124* was silenced in more than 10 types of cancer, as breast, colorectal, liver, and lung cancer. This silencing promotes increased expression of *CDK6*, which affects the phosphorylation state of *Rb* protein, favoring tumor progression [42]. Other miRs silenced are *miR-9-1* and *miR-9-3*. When analyzing the expression of *miR-9-3* in primary and metastatic tumors, it was observed that metastatic tumors have a lower expression of *miR-9-3*. Also, patients with lower *miR-9-3* expression in the tumor have a lower survival rate than patients with higher expression of *miR-9-3* [43].

Garzon et al. [40] observed that there is a decrease in *miRs-15a/16* expression in patients with chronic lymphoid leukemia and in chronic lymphocytic leukemia tumor cells CLL23. Thus, the authors ectopically increased the expression of *miRs-15a/16* in CLL23 tumor cells and investigated the processes of proliferation and apoptosis. It was observed that with the increase of *miRs-15a/16* expression in CLL23 tumor cells, there is a higher apoptosis and less cellular proliferation. This response occurs because *miRs-15a/16* target *BCL-2* protein, an important antiapoptotic factor. *BCL-2* is known to be increased in tumors of cancer patients [40].

Moreover, *miR-34* has been shown to be downregulated in pancreatic cancer. The overexpression of *miR-34* in these cells increases apoptosis and inhibition of autophagy, reducing tumor growth [44]. Another example is the miR *Let-7* family, which targets *HRAS* and *HMGA2* as well as participates in the regulation of proliferation and cell cycle. *Let-7* family members are also negatively regulated in various types of cancers, and their overexpression results in inhibition of tumor growth in different cancer models [45, 46]. This is due to the fact that *Let-7* targets the major components of cell cycle progression, such as *KRAS*, *CCDN1*, *CDC34*, *HMGA2*, *E2F2,* and *Lin28* [45, 46].

In contrast, miRs may also be increased in cancer and their biological effects may potentiate the development of the disease. For example, the case of *miR-21* has a high expression in tumors of glioblastoma, pancreatic cancer, breast cancer, and colon cancer. Inhibition of *miR-21* in glioblastoma cells was able to increase caspase activity and promote apoptosis of tumor cells. One possible explanation is that *miR-21* targets *PTEN* protein and *PDCD4* protein, functioning as an antiapoptotic agent in cancer [47].

MiRs are also involved in several other cancer factors, such as in the formation of metastases. Zhou et al. [48] observed that *miR-105* is involved with preparation of the "premetastatic niche." The authors demonstrated that animals with breast cancer exhibit high levels of *miR-105* expression in both tumor and circulation and that elevated *miR-105* levels in the circulation promote the destruction of endothelial barriers and increase vascular permeability in the target metastatic organ. Inhibition of *miR-105* in tumor cells from highly metastatic breast cancer prevented the development of

**27**

**Figure 2.**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

metastasis [48]. Another miR associated with metastasis formation is the family of *miR-200*. The 200 family plays a role in repress proteins that promote the epithelialmesenchymal transition. However, its expression is reduced in tumors in response to increased expression of the *long noncoding RNA ATB* that competes with the miRs binding site of the 200 family, reducing its expression and function, which favors the negative regulation of *E-cadherin* and increase of *ZEB* proteins expression [49]. The current involvement of miRs in the hallmarks of cancer is elucidated in **Figure 2**.

Although in recent time cancer treatments have evolved considerably, there are still no responsive patients to the treatments, which suggest the need for strategies to reduce the incidence and aggressiveness of cancer. At same time, *American Cancer Society* recommends to cancer survivors the participation in 150 min of moderate intensity exercise per week. There is evidence that physical activity improves quality of life, treatment response, decreases cancer recurrence due physical fitness improvement of patients, and survivors [50]. In the present moment, there is strong academic effort in clinical trials being performed, investigating about perspective and limitation of inclusion physical activities in the cancer therapy. The main investigations focus in physiological aspects and appropriate modalities and methods [51–53].

*Landscape of investigative field involving miRs, molecular basis, and the hallmarks of cancer. Currently, among the miRs related to the cancer hallmarks, only miR-21 and its target, the mRNA of PDCD4, PTEN, TPM1, HIF1α and VEGF was established the beneficial relationship with the effects of physical activity in the* 

*tumor (thin green arrows) [43–49, 83, 84]. https://smart.servier.com/image-set-download/.*

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

**4.1 Physical activity as nonpharmacological therapy**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia… DOI: http://dx.doi.org/10.5772/intechopen.84847*

metastasis [48]. Another miR associated with metastasis formation is the family of *miR-200*. The 200 family plays a role in repress proteins that promote the epithelialmesenchymal transition. However, its expression is reduced in tumors in response to increased expression of the *long noncoding RNA ATB* that competes with the miRs binding site of the 200 family, reducing its expression and function, which favors the negative regulation of *E-cadherin* and increase of *ZEB* proteins expression [49]. The current involvement of miRs in the hallmarks of cancer is elucidated in **Figure 2**.

## **4.1 Physical activity as nonpharmacological therapy**

Although in recent time cancer treatments have evolved considerably, there are still no responsive patients to the treatments, which suggest the need for strategies to reduce the incidence and aggressiveness of cancer. At same time, *American Cancer Society* recommends to cancer survivors the participation in 150 min of moderate intensity exercise per week. There is evidence that physical activity improves quality of life, treatment response, decreases cancer recurrence due physical fitness improvement of patients, and survivors [50]. In the present moment, there is strong academic effort in clinical trials being performed, investigating about perspective and limitation of inclusion physical activities in the cancer therapy. The main investigations focus in physiological aspects and appropriate modalities and methods [51–53].

#### **Figure 2.**

*Epigenetics*

**4. microRNAs and cancer**

higher expression of *miR-9-3* [43].

*E2F2,* and *Lin28* [45, 46].

agent in cancer [47].

The miRs play a key role in the control of various physiological and pathological processes. Many studies demonstrate the participation of miRs during the progression of several types of cancer. MiRs present altered expression in tumors, and many studies are being conducted with this new class of molecules to elucidate their

There is evidence that miRs are also involved in regulation of hallmarks of cancer and thus in the progression of cancer [5, 15]. In view of this, there is an effort by the scientific community to understand the mechanisms involving miRs and the development of cancer aiming to develop cancer-specific gene therapies [40]. The aim of these efforts is to improve responses to conventional drugs for the cancer treatment, specifically suppress oncogenic processes, and improve the prognosis of the disease. The *miR-124* was one of the first studied miRs involved in the pathogenesis of cancer [41]. *MiR-124* was silenced in more than 10 types of cancer, as breast, colorectal, liver, and lung cancer. This silencing promotes increased expression of *CDK6*, which affects the phosphorylation state of *Rb* protein, favoring tumor progression [42]. Other miRs silenced are *miR-9-1* and *miR-9-3*. When analyzing the expression of *miR-9-3* in primary and metastatic tumors, it was observed that metastatic tumors have a lower expression of *miR-9-3*. Also, patients with lower *miR-9-3* expression in the tumor have a lower survival rate than patients with

Garzon et al. [40] observed that there is a decrease in *miRs-15a/16* expression in patients with chronic lymphoid leukemia and in chronic lymphocytic leukemia tumor cells CLL23. Thus, the authors ectopically increased the expression of *miRs-15a/16* in CLL23 tumor cells and investigated the processes of proliferation and apoptosis. It was observed that with the increase of *miRs-15a/16* expression in CLL23 tumor cells, there is a higher apoptosis and less cellular proliferation. This response occurs because *miRs-15a/16* target *BCL-2* protein, an important antiapoptotic factor. *BCL-2* is known to be increased in tumors of cancer patients [40]. Moreover, *miR-34* has been shown to be downregulated in pancreatic cancer. The overexpression of *miR-34* in these cells increases apoptosis and inhibition of autophagy, reducing tumor growth [44]. Another example is the miR *Let-7* family, which targets *HRAS* and *HMGA2* as well as participates in the regulation of proliferation and cell cycle. *Let-7* family members are also negatively regulated in various types of cancers, and their overexpression results in inhibition of tumor growth in different cancer models [45, 46]. This is due to the fact that *Let-7* targets the major components of cell cycle progression, such as *KRAS*, *CCDN1*, *CDC34*, *HMGA2*,

In contrast, miRs may also be increased in cancer and their biological effects may potentiate the development of the disease. For example, the case of *miR-21* has a high expression in tumors of glioblastoma, pancreatic cancer, breast cancer, and colon cancer. Inhibition of *miR-21* in glioblastoma cells was able to increase caspase activity and promote apoptosis of tumor cells. One possible explanation is that *miR-21* targets *PTEN* protein and *PDCD4* protein, functioning as an antiapoptotic

MiRs are also involved in several other cancer factors, such as in the formation of metastases. Zhou et al. [48] observed that *miR-105* is involved with preparation of the "premetastatic niche." The authors demonstrated that animals with breast cancer exhibit high levels of *miR-105* expression in both tumor and circulation and that elevated *miR-105* levels in the circulation promote the destruction of endothelial barriers and increase vascular permeability in the target metastatic organ. Inhibition of *miR-105* in tumor cells from highly metastatic breast cancer prevented the development of

role in controlling the pathophysiology of the disease [36, 38, 39].

**26**

*Landscape of investigative field involving miRs, molecular basis, and the hallmarks of cancer. Currently, among the miRs related to the cancer hallmarks, only miR-21 and its target, the mRNA of PDCD4, PTEN, TPM1, HIF1α and VEGF was established the beneficial relationship with the effects of physical activity in the tumor (thin green arrows) [43–49, 83, 84]. https://smart.servier.com/image-set-download/.*

Physical fitness is the ability to perform daily tasks with vigor and alertness, without excessive fatigue and with energy to enjoy leisure activities and to meet unforeseen emergencies [54]. It is known that physical activity induces beneficial adaptations to the body, improving physical fitness [55]. Physical activity encompasses both physical exercise with controlled volume, intensity, and duration or recreational activities [56]. There is evidence that support the importance of maintaining a physically active life for health. Healthy individuals or cardiovascular patients who have low physical capacity tend to have a lower survival rate [57]. Corroborating with these clinical and epidemiological data, experimental results show that rats with high capacity to run present a higher survival (~45%) when compared to those that have low capacity to run [58, 59]. Regular physical activities are recognized as nonpharmacologic preventive approach and treatment for chronic diseases [60–62], including cancer [63–65]. Several studies also demonstrate that aerobic physical activity normalizes the expression of aberrant miRs due to diseases such as myocardial infarction, hypertension, diabetes, and obesity. That these pathologies induce molecular and structural alterations and aerobic physical exercise is a beneficial stimulus for the reversal and control of these deleterious alterations such as muscle mass decrease and microvascular rarefaction [66–69].

## **4.2 Physical activity, cancer, and microRNAs: new perspectives**

There is evidence that aerobic physical activity reduces the incidence of several types of cancer [65]. Moore et al. [65] demonstrated that regular physical activity resulted in decreased incidence of 13 types of cancer in 26 analyzed in 1.44 million adults. The individuals involved with higher daily volumes of physical activity presented decrease in the incidence in esophageal adenocarcinoma, myeloid leukemia, myeloma, liver, lung, kidney, gastric, endometrial, colon, head and neck, rectal, bladder, and breast cancer. The effects of physical activity on reducing the incidence of cancer were independent of other factors such as body mass index (BMI), smoking, geographical region, use of hormonal therapy, and ethnicity [65]. Cancer patients with reduced physical capacity have a worse prognosis [70–72]. Colon cancer patients have a reduction of more than 20% in maximal oxygen consumption (VO2 máx.) compared to their healthy peers [71]. Patients with lung cancer and colon cancer with greater physical capacity present a higher survival compared to patients with lower physical capacity [73]. Aerobic physical activity attenuates tumor growth in different animal models [74–78]. However, the molecular mechanisms involved in this response are poorly understood. Recently, Pedersen et al. [79] showed that 4 weeks of prior voluntary physical activity was able to delay tumor initiation and attenuate tumor growth in various cancer models in mice and was also efficient in decreasing the formation of metastatic nodules. The authors demonstrated that physical activity increases the mobilization and redistribution of NK cells to the tumor microenvironment due to the systemic increase of *IL-6* and epinephrine induced by physical activity. This increase of immune response in the tumor microenvironment was proposed as the main mechanism induced by aerobic physical activity for the attenuation of tumor growth [79]. Betof et al. [77] also demonstrated that previous aerobic physical activity is capable of attenuating tumor growth in the 4T1 breast cancer model. The authors demonstrated that aerobic physical activity increased the pericytic coverage of tumor vessels and apoptosis of tumor cells, provided a greater functional neo-vascularization on the tumor endothelium, and consequently reduced the hypoxia regions in the tumor microenvironment [77]. Pigna et al. demonstrated that aerobic physical activity is also efficient in increasing the survival of animals injected with C26 (colon cancer) tumor cells lineages [80].

**29**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

However, it is important to note that only two of the studies that observed attenuation of tumor growth induced by aerobic physical activity investigated the role of miR in this response, both in mice breast cancer injected with MC4-L2. Khori et al. observed that aerobic physical activity was efficient in reducing *miR-21* gene expression in animal tumors, inhibiting proliferation and migration of tumor cells. In addition, the *miR-21* downregulation was associated with increase of gene and protein *PDCD4* expression and *TPM1*, two tumor suppressor genes [81]. Isanejad et al. [82] also demonstrated that aerobic physical activity reduces tumor growth and increased the gene expression levels of *miRs-206* and *let-7* in the mammary tumor. Moreover, exercise-increased expression of *miR-206* and *let-7* decreased in the levels of gene expression of *HIF-1α*, *CD31*, and *VEGF* in mice, suggesting an anti-angiogenic effect, which contributed to the decrease of tumor angiogenesis and growth [82]. Both Khori et al. and Isanejad et al. observed involvement of miRs in the aerobic physical activity response, which enhanced the effects of treatment with tamoxifen and letrozole, respectively, on tumor growth

These results indicate the potential of physical activity in modulating the decompensated miRs in the tumor. Also, we can point to the potential of physical activity to an improved miRs profile in the tumor, and their direct role in the reduction of the tumor growth and aggressiveness. However, currently there is a gap in elucidating about the global molecular mechanisms by which physical activity induces the phenotypical improvement. Therefore, the interaction between cancer, miRs and the effect of physical activity in the several cancer types is a promisor field of investigation that certainly will develop a lot of knowledge about preventive, therapeutic,

Cancer cachexia (CC) is a multifactorial syndrome characterized by continuous loss of muscle mass that can be conjugated or not by loss of fat mass. CC cannot be completely reversed by conventional nutritional support and leads to progressive functional disability [83]. The pathophysiology of CC is characterized by a negative protein balance, anorexia, and metabolic abnormalities [84]. CC individuals usually present with muscle weakness, asthenia and poor response to anticancer treatment,

Muscle atrophy in CC results from the imbalance in protein turnover due to exacerbated proteolytic activation, reduction of protein synthesis pathways, and

In this context, it is essential to understand the role of epigenetic factors in the loss of muscle mass in CC. There is massive evidence that epigenetic factors, for example histone acetylation, DNA methylation and miRs orchestrate processes such as muscle proliferation and differentiation, as well as skeletal muscle regenerative capacity [89–92]. To elucidate about the epigenetic factors that lead to the loss of muscle mass in CC also may contribute to the emergence of new therapies for the

In this section, we will approach about the role of miRs in the regulation of muscular trophism. Skeletal muscle presents a set of miRs that are enriched in this tissue and mediate mechanisms of proliferation, differentiation, and protein synthesis. These miRs are known as myomiRs [32]. The most studied myomiRs are the *-133a/b*, *−206,* and *−1 miRs*. These miRs are known to display target genes such as *IGF-1R*, known hypertrophic pathway promoters [32] and *PAX3* and *PAX7*, genes that regulates proliferation of satellite cells [93]. In another view, there are many

as well as the mechanisms by which physical activity acts is cancer.

all of these processes contributes to patient mortality [85, 86].

reduced regenerative capacity in skeletal muscle [87, 88].

prevention and treatment of the syndrome.

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

and molecular responses [81, 82].

**5. Cancer cachexia**

#### *A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia… DOI: http://dx.doi.org/10.5772/intechopen.84847*

However, it is important to note that only two of the studies that observed attenuation of tumor growth induced by aerobic physical activity investigated the role of miR in this response, both in mice breast cancer injected with MC4-L2. Khori et al. observed that aerobic physical activity was efficient in reducing *miR-21* gene expression in animal tumors, inhibiting proliferation and migration of tumor cells. In addition, the *miR-21* downregulation was associated with increase of gene and protein *PDCD4* expression and *TPM1*, two tumor suppressor genes [81]. Isanejad et al. [82] also demonstrated that aerobic physical activity reduces tumor growth and increased the gene expression levels of *miRs-206* and *let-7* in the mammary tumor. Moreover, exercise-increased expression of *miR-206* and *let-7* decreased in the levels of gene expression of *HIF-1α*, *CD31*, and *VEGF* in mice, suggesting an anti-angiogenic effect, which contributed to the decrease of tumor angiogenesis and growth [82]. Both Khori et al. and Isanejad et al. observed involvement of miRs in the aerobic physical activity response, which enhanced the effects of treatment with tamoxifen and letrozole, respectively, on tumor growth and molecular responses [81, 82].

These results indicate the potential of physical activity in modulating the decompensated miRs in the tumor. Also, we can point to the potential of physical activity to an improved miRs profile in the tumor, and their direct role in the reduction of the tumor growth and aggressiveness. However, currently there is a gap in elucidating about the global molecular mechanisms by which physical activity induces the phenotypical improvement. Therefore, the interaction between cancer, miRs and the effect of physical activity in the several cancer types is a promisor field of investigation that certainly will develop a lot of knowledge about preventive, therapeutic, as well as the mechanisms by which physical activity acts is cancer.

## **5. Cancer cachexia**

*Epigenetics*

Physical fitness is the ability to perform daily tasks with vigor and alertness, without excessive fatigue and with energy to enjoy leisure activities and to meet unforeseen emergencies [54]. It is known that physical activity induces beneficial adaptations to the body, improving physical fitness [55]. Physical activity encompasses both physical exercise with controlled volume, intensity, and duration or recreational activities [56]. There is evidence that support the importance of maintaining a physically active life for health. Healthy individuals or cardiovascular patients who have low physical capacity tend to have a lower survival rate [57]. Corroborating with these clinical and epidemiological data, experimental results show that rats with high capacity to run present a higher survival (~45%) when compared to those that have low capacity to run [58, 59]. Regular physical activities are recognized as nonpharmacologic preventive approach and treatment for chronic

diseases [60–62], including cancer [63–65]. Several studies also demonstrate that aerobic physical activity normalizes the expression of aberrant miRs due to diseases such as myocardial infarction, hypertension, diabetes, and obesity. That these pathologies induce molecular and structural alterations and aerobic physical exercise is a beneficial stimulus for the reversal and control of these deleterious alterations such as muscle mass decrease and microvascular rarefaction [66–69].

There is evidence that aerobic physical activity reduces the incidence of several types of cancer [65]. Moore et al. [65] demonstrated that regular physical activity resulted in decreased incidence of 13 types of cancer in 26 analyzed in 1.44 million adults. The individuals involved with higher daily volumes of physical activity presented decrease in the incidence in esophageal adenocarcinoma, myeloid leukemia, myeloma, liver, lung, kidney, gastric, endometrial, colon, head and neck, rectal, bladder, and breast cancer. The effects of physical activity on reducing the incidence of cancer were independent of other factors such as body mass index (BMI), smoking, geographical region, use of hormonal therapy, and ethnicity [65]. Cancer patients with reduced physical capacity have a worse prognosis [70–72]. Colon cancer patients have a reduction of more than 20% in maximal oxygen consumption (VO2 máx.) compared to their healthy peers [71]. Patients with lung cancer and colon cancer with greater physical capacity present a higher survival compared to patients with lower physical capacity [73]. Aerobic physical activity attenuates tumor growth in different animal models [74–78]. However, the molecular mechanisms involved in this response are poorly understood. Recently, Pedersen et al. [79] showed that 4 weeks of prior voluntary physical activity was able to delay tumor initiation and attenuate tumor growth in various cancer models in mice and was also efficient in decreasing the formation of metastatic nodules. The authors demonstrated that physical activity increases the mobilization and redistribution of NK cells to the tumor microenvironment due to the systemic increase of *IL-6* and epinephrine induced by physical activity. This increase of immune response in the tumor microenvironment was proposed as the main mechanism induced by aerobic physical activity for the attenuation of tumor growth [79]. Betof et al. [77] also demonstrated that previous aerobic physical activity is capable of attenuating tumor growth in the 4T1 breast cancer model. The authors demonstrated that aerobic physical activity increased the pericytic coverage of tumor vessels and apoptosis of tumor cells, provided a greater functional neo-vascularization on the tumor endothelium, and consequently reduced the hypoxia regions in the tumor microenvironment [77]. Pigna et al. demonstrated that aerobic physical activity is also efficient in increasing the survival of animals injected with C26 (colon cancer)

**4.2 Physical activity, cancer, and microRNAs: new perspectives**

**28**

tumor cells lineages [80].

Cancer cachexia (CC) is a multifactorial syndrome characterized by continuous loss of muscle mass that can be conjugated or not by loss of fat mass. CC cannot be completely reversed by conventional nutritional support and leads to progressive functional disability [83]. The pathophysiology of CC is characterized by a negative protein balance, anorexia, and metabolic abnormalities [84]. CC individuals usually present with muscle weakness, asthenia and poor response to anticancer treatment, all of these processes contributes to patient mortality [85, 86].

Muscle atrophy in CC results from the imbalance in protein turnover due to exacerbated proteolytic activation, reduction of protein synthesis pathways, and reduced regenerative capacity in skeletal muscle [87, 88].

In this context, it is essential to understand the role of epigenetic factors in the loss of muscle mass in CC. There is massive evidence that epigenetic factors, for example histone acetylation, DNA methylation and miRs orchestrate processes such as muscle proliferation and differentiation, as well as skeletal muscle regenerative capacity [89–92]. To elucidate about the epigenetic factors that lead to the loss of muscle mass in CC also may contribute to the emergence of new therapies for the prevention and treatment of the syndrome.

In this section, we will approach about the role of miRs in the regulation of muscular trophism. Skeletal muscle presents a set of miRs that are enriched in this tissue and mediate mechanisms of proliferation, differentiation, and protein synthesis. These miRs are known as myomiRs [32]. The most studied myomiRs are the *-133a/b*, *−206,* and *−1 miRs*. These miRs are known to display target genes such as *IGF-1R*, known hypertrophic pathway promoters [32] and *PAX3* and *PAX7*, genes that regulates proliferation of satellite cells [93]. In another view, there are many

studies showing the role of several other miRs orchestrating prohypertrophic and procatabolic genes in the skeletal muscle [32, 94].

Interesting advances have been made in studies about the of role skeletal muscle enriched miRs in CC. Lee et al. [95] conducted a study in order to investigate the profile of miRs expressed in skeletal muscle of cachectic mice. The researchers performed a sequencing of the anterior tibial muscle of LLC tumor-bearing mice, animal model of orthotopic lung cancer, and compared them to healthy mice. The *miRs-147-3p*, *−299a-3p*, *1933-3p*, *511-3p*, *3473d*, *233-3p*, *431-5p*, *665-3p*, and *205-3p* were found to be differently expressed. Genetic ontology analyzes of these miRs indicate a relationship with cellular survival pathways, inflammatory response, cell cycle, cell development, and cell morphology through crosstalk of several pathways, with target genes such as *FOXO3*, *HRAS*, *P38*, *MAPK*, *MYC,* and *EIF4E*. We can note that *HRAS* and *MYC* are also related to hallmarks of cancer [95].

Narasimhan et al. [96] conducted another study evaluating the profile of miRs in muscle tissue of CC patients. In this study, human rectal abdominal muscle samples were collected during the tumor resection surgery of colon and pancreatic cancer patients. Sequencing analyzes demonstrated that eight miRs were differentially expressed between cachectic individuals and controls. The miRs let-*7d-3p*, *3184-3p,* and *−1296-5p* were selected and these miRs were increased in cachectic patients relative to controls. The authors performed *in*-*silico* analyzes and pointed out that these miRs targets genes related to adipogenesis, myogenesis (*SULF1* and *DLK1*), inflammation, and immune response (*RPS6KA6*) [96].

The loss of fat mass is not present in all cases of CC; however, the role in energy metabolism of adipose tissue in CC is important. Therefore, studies are being conducted to understand the function of miRs in maintaining of adipose tissue in cachetic state. Kulyté et al. [97] conducted a sequencing analyzes of miRs in adipose tissue of cachectic and noncachectic gastrointestinal cancer patients, the authors found difference in expression of nine miRs between cachectic and noncachectic patients. *MiR-378* was selected due to an increased expression in the adipose tissue of cachectic patients compared to noncachectic patients. The inhibition and overexpression of *miR-378* on human adipose-derived stem cells were performed; overexpression of *miR-378* decreased expression of the *HSL*, *PLIN1*, and *ATGL* protein and consequently increased lipids catabolism and release of glycerol [97].

MiRs are also present in body fluids such as saliva, tear, and blood. In this sense, studies are being conducted with the purpose of understanding the role of circulating miRs in CC. Okugawa et al. [98] showed that the expression of circulating *miR-21* increases in the patients with cachectic colon cancer; however, the expression of *miR-21* is not different in the skeletal muscle in compared to noncachectic patients [98]. The circulating miRs can be studied as biomarkers for some pathological processes. Studies in humans and animals have looked for miRs that are biomarkers in order to early diagnose CC [94]; however, it should be noted that many of these miRs are not widely accepted as biomarkers by the medical and scientific community and some are not even validated in humans [96].

The role of *miR-21* in CC was also investigated by He et al. [99], which showed that *miR-21*-enriched exosomes were found in the circulation of pancreatic and lung cancer patients. Myoblast cells cultures treated with these *miR-21*-enriched exosomes showed an interaction of the microvesicle with the muscle cells that induced cell death via *TLR8* protein, an endosomal receptor that recognizes single-stranded RNA (ssRNA), and can recognize ssRNA viruses such as Influenza, Sendai, and Coxsackie B viruses. *TLR8* is a protein binding to RNA and is able to recruit *MYD88* and leads to activation of the transcription factor *NF-κB* and an antiviral response. *TLR8* agonists have undergone clinical trials as immune stimulants in combination therapy for some cancers [99].

**31**

**6. Conclusions**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

There are few studies showing a direct association of the action of miRs and their targets about processes involved in the progression or reversal of CC. The issue promises a great field for development of results that can be clinically relevant and useful in the future. Additionally, skeletal muscle is highly responsive to both physical activity and CC, and investigation of skeletal muscle-enriched miRs and the effect of physical activity and exercise in these miRs are promising to elucidate

**5.1 Relationship between physical exercise and the mediators of cachexia**

There is massive evidence that support the importance of maintaining aerobic fitness for health. Low aerobic fitness is an independent indicator of early death in individuals with cardiovascular and/or healthy individuals [57]. The physical training regulates the expression of miRs in a profile that enables endurance performance and physical fitness. Aerobic exercise prevents a number of chronic-degenerative diseases [60], including cancer [65]. Resistance training increases muscle mass and strength and contributes to increased functional capacity [87]. Therefore, aerobic and resistance training are presented as a therapeutic potential for CC patients and presents an interesting field of investigation to clarify clinically relevant process related to CC. However, due to clinical difficulties and poor safety conditions, there is a lack in human studies about the role of physical exercise in CC patients. In this context, the use of animal models in well-controlled studies has shown that physical training may be promising in the treatment of CC. Oh et al. demonstrated that the C26, orthotopic colon cancer cachectic mice, when submitted to resistance training and aerobic training protocols presented lower muscle mass loss [100]. Partial preservation of muscle mass due to physical training is associated with higher expression of proteins such as *mTOR*, *IGF,* and *myogenin* in the trained C26 mice when compared to sedentary C26 mice [100]. Pigna et al. demonstrated that voluntary aerobic activity in C26 mice also improves the autophagy flow preventing skeletal muscle loss in association with autophagy regulatory drugs [80]. Baggish et al. showed for the first time that *miRs-21*, *miR-146a,* and *-133a* are candidates to be biomarkers of

Skeletal muscle trophism is regulated by the action of some miRs, and exercise controls the expression of these miRs. As example, *IGF-IR* mRNA encodes *IGF1* receptor protein and is a target of *miR-133*. A study shows that *IGF-IR* overexpression results in increased PI3K-AKT-mTOR pathway that mediated muscle hypertrophy, in myocyte cell culture, and that knockdown of *IGF-IR* decreases the hypertrophic signal. *MiR-133* decreases the expression of *IGF-IR*, and consequently decreases *AKT* and *mTOR* phosphorylation, regulating the development of skeletal muscle [102]. Furthermore, aerobic physical exercise decreases the expression of *miR-133a* [103]. In conclusion, many studies show that both aerobic and resistance physical exercise control the expression of miRs that are dysregulated by diseases as hypertension, diabetes, and obesity [68, 69, 104, 105]. Physical exercise rebalances the expression of the miRs involved with those alterations reverses structural deleterious changes in the skeletal muscle and restores tissue or prevents deterioration [66]. However, there are no studies designing an miR profile from CC skeletal muscle and the prevention of muscle catabolism by physical exercise, which is interesting for future investigation.

The effects of physical activity as nonpharmacological adjuvant for cancer patients are effective to the disease and survivorship in cancer, since it improves

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

about CC. The next section will cover this topic.

aerobic physical training in the circulation [101].

#### *A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia… DOI: http://dx.doi.org/10.5772/intechopen.84847*

There are few studies showing a direct association of the action of miRs and their targets about processes involved in the progression or reversal of CC. The issue promises a great field for development of results that can be clinically relevant and useful in the future. Additionally, skeletal muscle is highly responsive to both physical activity and CC, and investigation of skeletal muscle-enriched miRs and the effect of physical activity and exercise in these miRs are promising to elucidate about CC. The next section will cover this topic.

## **5.1 Relationship between physical exercise and the mediators of cachexia**

There is massive evidence that support the importance of maintaining aerobic fitness for health. Low aerobic fitness is an independent indicator of early death in individuals with cardiovascular and/or healthy individuals [57]. The physical training regulates the expression of miRs in a profile that enables endurance performance and physical fitness. Aerobic exercise prevents a number of chronic-degenerative diseases [60], including cancer [65]. Resistance training increases muscle mass and strength and contributes to increased functional capacity [87]. Therefore, aerobic and resistance training are presented as a therapeutic potential for CC patients and presents an interesting field of investigation to clarify clinically relevant process related to CC. However, due to clinical difficulties and poor safety conditions, there is a lack in human studies about the role of physical exercise in CC patients. In this context, the use of animal models in well-controlled studies has shown that physical training may be promising in the treatment of CC. Oh et al. demonstrated that the C26, orthotopic colon cancer cachectic mice, when submitted to resistance training and aerobic training protocols presented lower muscle mass loss [100]. Partial preservation of muscle mass due to physical training is associated with higher expression of proteins such as *mTOR*, *IGF,* and *myogenin* in the trained C26 mice when compared to sedentary C26 mice [100]. Pigna et al. demonstrated that voluntary aerobic activity in C26 mice also improves the autophagy flow preventing skeletal muscle loss in association with autophagy regulatory drugs [80]. Baggish et al. showed for the first time that *miRs-21*, *miR-146a,* and *-133a* are candidates to be biomarkers of aerobic physical training in the circulation [101].

Skeletal muscle trophism is regulated by the action of some miRs, and exercise controls the expression of these miRs. As example, *IGF-IR* mRNA encodes *IGF1* receptor protein and is a target of *miR-133*. A study shows that *IGF-IR* overexpression results in increased PI3K-AKT-mTOR pathway that mediated muscle hypertrophy, in myocyte cell culture, and that knockdown of *IGF-IR* decreases the hypertrophic signal. *MiR-133* decreases the expression of *IGF-IR*, and consequently decreases *AKT* and *mTOR* phosphorylation, regulating the development of skeletal muscle [102]. Furthermore, aerobic physical exercise decreases the expression of *miR-133a* [103].

In conclusion, many studies show that both aerobic and resistance physical exercise control the expression of miRs that are dysregulated by diseases as hypertension, diabetes, and obesity [68, 69, 104, 105]. Physical exercise rebalances the expression of the miRs involved with those alterations reverses structural deleterious changes in the skeletal muscle and restores tissue or prevents deterioration [66]. However, there are no studies designing an miR profile from CC skeletal muscle and the prevention of muscle catabolism by physical exercise, which is interesting for future investigation.

## **6. Conclusions**

The effects of physical activity as nonpharmacological adjuvant for cancer patients are effective to the disease and survivorship in cancer, since it improves

*Epigenetics*

studies showing the role of several other miRs orchestrating prohypertrophic and

can note that *HRAS* and *MYC* are also related to hallmarks of cancer [95].

*DLK1*), inflammation, and immune response (*RPS6KA6*) [96].

nity and some are not even validated in humans [96].

in muscle tissue of CC patients. In this study, human rectal abdominal muscle samples were collected during the tumor resection surgery of colon and pancreatic cancer patients. Sequencing analyzes demonstrated that eight miRs were differentially expressed between cachectic individuals and controls. The miRs let-*7d-3p*, *3184-3p,* and *−1296-5p* were selected and these miRs were increased in cachectic patients relative to controls. The authors performed *in*-*silico* analyzes and pointed out that these miRs targets genes related to adipogenesis, myogenesis (*SULF1* and

Narasimhan et al. [96] conducted another study evaluating the profile of miRs

The loss of fat mass is not present in all cases of CC; however, the role in energy

The role of *miR-21* in CC was also investigated by He et al. [99], which showed that *miR-21*-enriched exosomes were found in the circulation of pancreatic and lung cancer patients. Myoblast cells cultures treated with these *miR-21*-enriched exosomes showed an interaction of the microvesicle with the muscle cells that induced cell death via *TLR8* protein, an endosomal receptor that recognizes single-stranded RNA (ssRNA), and can recognize ssRNA viruses such as Influenza, Sendai, and Coxsackie B viruses. *TLR8* is a protein binding to RNA and is able to recruit *MYD88* and leads to activation of the transcription factor *NF-κB* and an antiviral response. *TLR8* agonists have undergone clinical trials as immune stimulants in combination

metabolism of adipose tissue in CC is important. Therefore, studies are being conducted to understand the function of miRs in maintaining of adipose tissue in cachetic state. Kulyté et al. [97] conducted a sequencing analyzes of miRs in adipose tissue of cachectic and noncachectic gastrointestinal cancer patients, the authors found difference in expression of nine miRs between cachectic and noncachectic patients. *MiR-378* was selected due to an increased expression in the adipose tissue of cachectic patients compared to noncachectic patients. The inhibition and overexpression of *miR-378* on human adipose-derived stem cells were performed; overexpression of *miR-378* decreased expression of the *HSL*, *PLIN1*, and *ATGL* protein and consequently increased lipids catabolism and release of glycerol [97]. MiRs are also present in body fluids such as saliva, tear, and blood. In this sense, studies are being conducted with the purpose of understanding the role of circulating miRs in CC. Okugawa et al. [98] showed that the expression of circulating *miR-21* increases in the patients with cachectic colon cancer; however, the expression of *miR-21* is not different in the skeletal muscle in compared to noncachectic patients [98]. The circulating miRs can be studied as biomarkers for some pathological processes. Studies in humans and animals have looked for miRs that are biomarkers in order to early diagnose CC [94]; however, it should be noted that many of these miRs are not widely accepted as biomarkers by the medical and scientific commu-

Interesting advances have been made in studies about the of role skeletal muscle enriched miRs in CC. Lee et al. [95] conducted a study in order to investigate the profile of miRs expressed in skeletal muscle of cachectic mice. The researchers performed a sequencing of the anterior tibial muscle of LLC tumor-bearing mice, animal model of orthotopic lung cancer, and compared them to healthy mice. The *miRs-147-3p*, *−299a-3p*, *1933-3p*, *511-3p*, *3473d*, *233-3p*, *431-5p*, *665-3p*, and *205-3p* were found to be differently expressed. Genetic ontology analyzes of these miRs indicate a relationship with cellular survival pathways, inflammatory response, cell cycle, cell development, and cell morphology through crosstalk of several pathways, with target genes such as *FOXO3*, *HRAS*, *P38*, *MAPK*, *MYC,* and *EIF4E*. We

procatabolic genes in the skeletal muscle [32, 94].

**30**

therapy for some cancers [99].

quality of life and decreases the recurrence of cancer. Currently, there are massive efforts to include exercise in the therapeutic approach to patients. Furthermore, studies show several benefits of aerobic physical activity in reducing the risk of incidence of cancer. Physical activity also reduces expenditures for public health agencies, both by decrease of cancer incidence and can attenuate the side effects or resistance related to anticancer treatment. However, little is known about the epigenetic, molecular, and cellular mechanisms involved in this response, both related to hallmarks of cancer, to cachexia process, and the comprehension about physical training effect in oncologic patients remains incipient.

Recently, the attentions of several areas of the scientific community have turned to miRs, epigenetic regulators in different cellular processes, as in tumorigenesis. To date, studies postulating the effects of aerobic physical activity on the modulation of decompensated miRNAs in the tumor and its potential as cancer gene therapy in cancer are rare. Thus, the identification of miRs modified by cancer of sedentary animals in comparison with trained animals can lead to the identification of miRs with therapeutic potential and elucidate about epigenetic mechanisms involved in physical activity therapy. However, it is necessary to better understand these mechanisms both in cell culture and in animal models of cancer in order to transpose into translational medicine in a whole approach. In this sense, extensive basic research is needed to elucidate these mechanisms in order to establish relationships about the role of miRs, the 10 biological capacities, the hallmarks of cancer, and if how these processes can be reversed by physical activity. Another interesting issue to be investigated is about the involvement of the miRs regulated by the physical activity in the CC and how these miRs are related to the 10 capacities and the hallmarks of cancer. These approaches can extensively clarify about cancer mechanisms and improve future physical activity therapy.

## **Acknowledgements**

The researchers were supported by Sao Paulo Research Foundation (FAPESP: 2015/22814-5, 2015/17275-8, 2015/09919-2, 2017/22069-3, and 2018/02351-9), USP/ PRP-NAPmiR, National Council for Scientific and Technological Development (CNPq: 307591/2009-3, 159827/2011-6, and 313479/2017-8), and Coordination for the Improvement of Higher Education Personnel (CAPES-Proex).

## **Conflict of interest**

No disclosures.

## **Abbreviations**


**33**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

DGCR8 DiGeorge syndrome critical region gene 8 microprocessor protein

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

CDK6 cell division protein kinase 6

DLK1 delta like non-canonical Notch ligand 1

EIF4E eukaryotic translation initiation factor 4E EMT epithelial-mesenchymal transition

CDC34 cell division cycle 34

DNA deoxyribonucleic acid E2F2 E2F transcription factor 2

ETS1 ETS proto-oncogene 1 FOXO3 forkhead box O3

HRAS HRas proto-oncogene HSL hormone-sensitive lipase IGF insulin-like growth factor

IL-6 interleukin 6

mRNA messenger RNA miR microRNA

MYC Myc proto-oncogene

alpha

PDCD4 programmed cell death 4 RISC RNA induced silencer complex RPS6KA6 ribosomal protein S6 kinase A6

NK cells natural killer cells

PAX3 paired box 3 PAX7 paired box 7

PLIN1 perilipin 1

SULF1 sulfatase 1

TLR8 toll like receptor 8 TPM1 tropomyosin 1

ZO1 tight junction protein 1

HDL high-density lipoprotein

HiF1α hypoxia inducible factor 1 alpha HMGA2 high-mobility group AT-hook 2

IGF-1R insulin like growth factor 1 receptor

mTOR mechanistic target of rapamycin kinase

MyD88 myeloid differentiation primary response

PI3K phosphatidylinositol-4,5-bisphosphate 3-kinase

PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit

P38 mitogen-activated protein kinase 14

PDCD4 programmed cell death protein 4 PTEN phosphatase and tensin homolog

VEGF vascular endothelial growth factor

MAPK mitogen-activated protein kinase VO2máx maximal oxygen consumption

CD324 cadherin 1

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia… DOI: http://dx.doi.org/10.5772/intechopen.84847*


*Epigenetics*

quality of life and decreases the recurrence of cancer. Currently, there are massive efforts to include exercise in the therapeutic approach to patients. Furthermore, studies show several benefits of aerobic physical activity in reducing the risk of incidence of cancer. Physical activity also reduces expenditures for public health agencies, both by decrease of cancer incidence and can attenuate the side effects or resistance related to anticancer treatment. However, little is known about the epigenetic, molecular, and cellular mechanisms involved in this response, both related to hallmarks of cancer, to cachexia process, and the comprehension about physical

Recently, the attentions of several areas of the scientific community have turned to miRs, epigenetic regulators in different cellular processes, as in tumorigenesis. To date, studies postulating the effects of aerobic physical activity on the modulation of decompensated miRNAs in the tumor and its potential as cancer gene therapy in cancer are rare. Thus, the identification of miRs modified by cancer of sedentary animals in comparison with trained animals can lead to the identification of miRs with therapeutic potential and elucidate about epigenetic mechanisms involved in physical activity therapy. However, it is necessary to better understand these mechanisms both in cell culture and in animal models of cancer in order to transpose into translational medicine in a whole approach. In this sense, extensive basic research is needed to elucidate these mechanisms in order to establish relationships about the role of miRs, the 10 biological capacities, the hallmarks of cancer, and if how these processes can be reversed by physical activity. Another interesting issue to be investigated is about the involvement of the miRs regulated by the physical activity in the CC and how these miRs are related to the 10 capacities and the hallmarks of cancer. These approaches can extensively clarify about cancer mechanisms and improve

The researchers were supported by Sao Paulo Research Foundation (FAPESP: 2015/22814-5, 2015/17275-8, 2015/09919-2, 2017/22069-3, and 2018/02351-9), USP/ PRP-NAPmiR, National Council for Scientific and Technological Development (CNPq: 307591/2009-3, 159827/2011-6, and 313479/2017-8), and Coordination for

the Improvement of Higher Education Personnel (CAPES-Proex).

ATGL patatin-like phospholipase domain-containing protein 2

training effect in oncologic patients remains incipient.

future physical activity therapy.

**Acknowledgements**

**Conflict of interest**

No disclosures.

3'UTR region 3' untranslated region AKT AKT serine/threonine kinase

AGO argonaute protein

BCL2 B-cell lymphoma 2 BMI body mass index CC cancer cachexia CCDN1 cyclin D1

**Abbreviations**

**32**

*Epigenetics*

## **Author details**

Gabriel Cardial Tobias, João Lucas Penteado Gomes, Ursula Paula Renó Soci, Tiago Fernandes and Edilamar Menezes de Oliveira\* School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil

\*Address all correspondence to: edilamar@usp.br

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**35**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. The American Journal of Clinical Nutrition.

[11] Anderson WF, Rosenberg PS, Prat A, Perou CM, Sherman ME. How many etiological subtypes of breast cancer: Two, three, four, or more? Journal of the National Cancer Institute.

[12] Lago CU, Sung HJ, Ma W, Wang P, Hwang PM. P53, aerobic metabolism, and cancer. Antioxidants & Redox Signaling. 2011;**15**(6):1739-1748

[13] Waning DL, Mohammad KS, Reiken S, Xie W, Andersson DC, John S, et al. Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nature Medicine.

[14] Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Medicine.

[15] Yuan J, Yang F, Wang F, Ma J, Guo Y, Tao Q, et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell.

[16] Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature.

[17] Pusapati RV, Daemen A, Wilson C, Sandoval W, Gao M, Haley B, et al. MTORC1-dependent metabolic reprogramming underlies escape from

2006;**83**(6):1345-1350

2014;**106**(8):1-11

2015;**21**(11):1262-1271

2012;**18**(6):883-891

2014;**25**(5):666-681

2005;**438**(7069):820-827

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

[2] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-tieulent J, Jemal A. Global Cancer Statistics, 2012. CA: A Cancer Journal for Clinicians. 2015;**65**(2):87-108

Immunological Reviews. 2004;**202**:8-32

microambiente tumoral [Cancer and the Tumor Microenvironment]. Revista Médica (Puebla). 2010;**89**(1):21-31

[5] Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell.

[7] Tisdale MJ. Reversing cachexia. Cell.

[8] Moses AWG, Slater C, Preston T, Barber MD, Fearon KCH. Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids. British Journal of Cancer.

[9] Bachmann J, Heiligensetzer M, Krakowski-Roosen H, Büchler MW, Friess H, Martignoni ME. Cachexia worsens prognosis in patients with resectable pancreatic cancer. Journal of Gastrointestinal Surgery.

[10] Fearon KC, Voss AC, Hustead DS. Definition of cancer cachexia: Effect

[1] Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA: A Cancer Journal for Clinicians. 2016;**66**(4):271-289

[3] Pestka S, Krause CD, Walter MR. Interferons, interferon-like cytokines, and their receptors.

[4] Chammas R. Câncer e o

2011;**144**(5):646-674

2000;**100**(7):57-70

2010;**142**(4):511-512

2004;**90**(5):996-1002

2008;**12**(7):1193-1201

[6] Hanahan D, Weinbreg. The hallmarks of cancer. Cell Press.

**References**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia… DOI: http://dx.doi.org/10.5772/intechopen.84847*

## **References**

*Epigenetics*

**34**

**Author details**

provided the original work is properly cited.

Tiago Fernandes and Edilamar Menezes de Oliveira\*

\*Address all correspondence to: edilamar@usp.br

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Gabriel Cardial Tobias, João Lucas Penteado Gomes, Ursula Paula Renó Soci,

School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil

[1] Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA: A Cancer Journal for Clinicians. 2016;**66**(4):271-289

[2] Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-tieulent J, Jemal A. Global Cancer Statistics, 2012. CA: A Cancer Journal for Clinicians. 2015;**65**(2):87-108

[3] Pestka S, Krause CD, Walter MR. Interferons, interferon-like cytokines, and their receptors. Immunological Reviews. 2004;**202**:8-32

[4] Chammas R. Câncer e o microambiente tumoral [Cancer and the Tumor Microenvironment]. Revista Médica (Puebla). 2010;**89**(1):21-31

[5] Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;**144**(5):646-674

[6] Hanahan D, Weinbreg. The hallmarks of cancer. Cell Press. 2000;**100**(7):57-70

[7] Tisdale MJ. Reversing cachexia. Cell. 2010;**142**(4):511-512

[8] Moses AWG, Slater C, Preston T, Barber MD, Fearon KCH. Reduced total energy expenditure and physical activity in cachectic patients with pancreatic cancer can be modulated by an energy and protein dense oral supplement enriched with n-3 fatty acids. British Journal of Cancer. 2004;**90**(5):996-1002

[9] Bachmann J, Heiligensetzer M, Krakowski-Roosen H, Büchler MW, Friess H, Martignoni ME. Cachexia worsens prognosis in patients with resectable pancreatic cancer. Journal of Gastrointestinal Surgery. 2008;**12**(7):1193-1201

[10] Fearon KC, Voss AC, Hustead DS. Definition of cancer cachexia: Effect

of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. The American Journal of Clinical Nutrition. 2006;**83**(6):1345-1350

[11] Anderson WF, Rosenberg PS, Prat A, Perou CM, Sherman ME. How many etiological subtypes of breast cancer: Two, three, four, or more? Journal of the National Cancer Institute. 2014;**106**(8):1-11

[12] Lago CU, Sung HJ, Ma W, Wang P, Hwang PM. P53, aerobic metabolism, and cancer. Antioxidants & Redox Signaling. 2011;**15**(6):1739-1748

[13] Waning DL, Mohammad KS, Reiken S, Xie W, Andersson DC, John S, et al. Excess TGF-β mediates muscle weakness associated with bone metastases in mice. Nature Medicine. 2015;**21**(11):1262-1271

[14] Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Medicine. 2012;**18**(6):883-891

[15] Yuan J, Yang F, Wang F, Ma J, Guo Y, Tao Q, et al. A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. Cancer Cell. 2014;**25**(5):666-681

[16] Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;**438**(7069):820-827

[17] Pusapati RV, Daemen A, Wilson C, Sandoval W, Gao M, Haley B, et al. MTORC1-dependent metabolic reprogramming underlies escape from glycolysis addiction in cancer cells. Cancer Cell. 2016;**29**(4):548-562

[18] Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing endogenous RNA. Cancer Cell. 2016;**29**(5):653-668

[19] Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, et al. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell. 2013;**23**(3):287-301

[20] Luo C, Lim JH, Lee Y, Granter SR, Thomas A, Vazquez F, et al. A PGC1α-mediated transcriptional axis suppresses melanoma metastasis. Nature. 2016;**537**(7620):422-426

[21] Lim JH, Luo C, Vazquez F, Puigserver P. Targeting mitochondrial oxidative metabolism in melanoma causes metabolic compensation through glucose and glutamine utilization. Cancer Research. 2014;**74**(13):3535-3545

[22] Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscleinvasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;**25**(2):152-165

[23] Lu F, Chen Y, Zhao C, Wang H, He D, Xu L, et al. Olig2-dependent reciprocal shift in PDGF and EGF receptor signaling regulates tumor phenotype and mitotic growth in malignant glioma. Cancer Cell. 2016;**29**(5):669-683

[24] Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, et al. Pre-metastatic niches: Organspecific homes for metastases. Nature Reviews Cancer. 2017

[25] Nebbioso A, Tambaro FP, Dell'Aversana C, Altucci L. Cancer epigenetics: Moving forward. PLoS Genetics. 2018;**14**(6):1-25

[26] Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science (80- ). 2017;**357**(6348)

[27] Murtha M, Esteller M. Extraordinary cancer epigenomics: Thinking outside the classical coding and promoter box. Trends in Cancer. 2016;**2**(10):572-584

[28] Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes & Development. 2009:23-25

[29] Muñoz-Pinedo C, González-Suárez E, Portela A, Gentilella A, Esteller M. Exploiting tumor vulnerabilities: Epigenetics, cancer metabolism and the mtor pathway in the era of personalized medicine. Cancer Research. 2013;**73**(14):4185-4189

[30] Bardhan K, Liu K. Epigenetics and colorectal cancer pathogenesis. Cancers (Basel). 2013;**5**(2):676-713

[31] Alderton GK. Tumour evolution: Epigenetic and genetic heterogeneity in metastasis. Nature Reviews. Cancer. 2017;**17**(3):141-141

[32] Horak M, Novak J, Bienertova-Vasku J. Muscle-specific microRNAs in skeletal muscle development. Developmental Biology. 2016;**410**(1):1-13

[33] Lee RC, Feinbaum RL, Ambros V. The *C. elegans* heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;**75**(5):843-854

[34] Hong Y, Lee RC, Ambros V. Structure and function analysis of LIN-14, a temporal regulator of postembryonic developmental events in

**37**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

[44] Gibori H, Eliyahu S, Krivitsky A, Ben-Shushan D, Epshtein Y, Tiram G, et al. Amphiphilic nanocarrierinduced modulation of PLK1 and MIR-34a leads to improved therapeutic response in pancreatic cancer. Nature

[45] Brueckner B, Stresemann C, Kuner R, Mund C, Musch T, Meister M, et al. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Research. 2007;**67**(4):1419-1423

[46] Wang T, Wang G, Hao D, Liu X, Wang D, Ning N, et al. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks

of cancer. Molecular Cancer.

[47] Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Research.

[48] Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell.

[49] Chan YC, Khanna S, Roy S, Sen CK. MiR-200b targets Ets-1 and is down-regulated by hypoxia to induce angiogenic response of endothelial cells. The Journal of Biological Chemistry.

2005;**65**(14):6029-6033

2014;**25**(4):501-515

2011;**286**(3):2047-2056

[50] Rock CL, Doyle C, Demark-

Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, et al. Nutrition and physical activity guidelines for cancer survivors. CA: A Cancer Journal for Cinicians. 2012;**62**(2):242-274

[51] Alibhai SMH, Santa Mina D, Ritvo P, Sabiston C, Krahn M, Tomlinson G, et al. A phase II RCT and economic

2015;**14**(1):1-13

Communications. 2018;**9**(1)

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

*Caenorhabditis elegans*. Molecular and Cellular Biology. 2000;**20**(6):2285-2295

[36] Bartel DP. Metazoan microRNAs. Cell [Internet]. 2018;**173**(1):20-51. DOI:

MicroRNAs. Circulation Research.

[38] Müller S, Nowak K. Exploring the miRNA-mRNA regulatory network in clear cell renal cell carcinomas by next-generation sequencing expression profiles. BioMed Research International.

[35] Ambros V. microRNAs: Tiny regulators with great potential. Cell.

2001;**107**(7):823-826

10.1016/j.cell.2018.03.006

[37] Creemers EE, Tijsen AJ, Pinto YM. Circulating

2014;**2014**(948408):1-11

2010;**48**(Suppl 2):1-6

2007;**67**(4):1424-1429

2013;**73**(2):473-477

2010;**29**(42):5724-5728

[39] Tutar Y. miRNA and cancer; computational and experimental approaches. Current Pharmaceutical Biotechnology. 2014;**15**(5):429

[40] Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: Rationale, strategies and challenges. Nature Reviews Clinical Oncology.

[41] Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setien F, et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Research.

[42] Baer C, Claus R, Plass C. Genome-

[43] Hildebrandt MAT, Gu J, Lin J, Ye Y, Tan W, Tamboli P, et al. Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma. Oncogene.

wide epigenetic regulation of miRNAs in cancer. Cancer Research.

2012;**110**(3):483-495

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia… DOI: http://dx.doi.org/10.5772/intechopen.84847*

*Caenorhabditis elegans*. Molecular and Cellular Biology. 2000;**20**(6):2285-2295

*Epigenetics*

glycolysis addiction in cancer cells. Cancer Cell. 2016;**29**(4):548-562

[25] Nebbioso A, Tambaro FP, Dell'Aversana C, Altucci L. Cancer epigenetics: Moving forward. PLoS

[26] Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science (80- ).

M. Extraordinary cancer epigenomics: Thinking outside the classical coding and promoter box. Trends in Cancer.

[29] Muñoz-Pinedo C, González-Suárez E, Portela A, Gentilella A, Esteller M. Exploiting tumor vulnerabilities: Epigenetics, cancer metabolism and the mtor pathway in the era of personalized

[30] Bardhan K, Liu K. Epigenetics and colorectal cancer pathogenesis. Cancers

[31] Alderton GK. Tumour evolution: Epigenetic and genetic heterogeneity in metastasis. Nature Reviews. Cancer.

[32] Horak M, Novak J, Bienertova-Vasku J. Muscle-specific microRNAs in skeletal muscle development. Developmental

[33] Lee RC, Feinbaum RL, Ambros V. The *C. elegans* heterochronic gene lin-4 encodes small RNAs with antisense

complementarity to lin-14. Cell.

[34] Hong Y, Lee RC, Ambros V. Structure and function analysis of LIN-14, a temporal regulator of postembryonic developmental events in

Genetics. 2018;**14**(6):1-25

[27] Murtha M, Esteller

2016;**2**(10):572-584

[28] Berger SL, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics. Genes & Development. 2009:23-25

medicine. Cancer Research. 2013;**73**(14):4185-4189

(Basel). 2013;**5**(2):676-713

Biology. 2016;**410**(1):1-13

2017;**17**(3):141-141

1993;**75**(5):843-854

2017;**357**(6348)

[18] Qu L, Ding J, Chen C, Wu ZJ, Liu B, Gao Y, et al. Exosome-transmitted lncARSR promotes sunitinib resistance in renal cancer by acting as a competing

[19] Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, et al. PGC1α expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell.

[20] Luo C, Lim JH, Lee Y, Granter SR, Thomas A, Vazquez F, et al. A PGC1α-mediated transcriptional axis suppresses melanoma metastasis. Nature. 2016;**537**(7620):422-426

[21] Lim JH, Luo C, Vazquez F,

Puigserver P. Targeting mitochondrial oxidative metabolism in melanoma causes metabolic compensation through glucose and glutamine utilization. Cancer Research. 2014;**74**(13):3535-3545

[22] Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscleinvasive bladder cancer with different sensitivities to frontline chemotherapy.

Cancer Cell. 2014;**25**(2):152-165

2016;**29**(5):669-683

Reviews Cancer. 2017

[23] Lu F, Chen Y, Zhao C, Wang H, He D, Xu L, et al. Olig2-dependent reciprocal shift in PDGF and EGF receptor signaling regulates tumor phenotype and mitotic growth in malignant glioma. Cancer Cell.

[24] Peinado H, Zhang H, Matei IR, Costa-Silva B, Hoshino A, Rodrigues G, et al. Pre-metastatic niches: Organspecific homes for metastases. Nature

endogenous RNA. Cancer Cell.

2016;**29**(5):653-668

2013;**23**(3):287-301

**36**

[35] Ambros V. microRNAs: Tiny regulators with great potential. Cell. 2001;**107**(7):823-826

[36] Bartel DP. Metazoan microRNAs. Cell [Internet]. 2018;**173**(1):20-51. DOI: 10.1016/j.cell.2018.03.006

[37] Creemers EE, Tijsen AJ, Pinto YM. Circulating MicroRNAs. Circulation Research. 2012;**110**(3):483-495

[38] Müller S, Nowak K. Exploring the miRNA-mRNA regulatory network in clear cell renal cell carcinomas by next-generation sequencing expression profiles. BioMed Research International. 2014;**2014**(948408):1-11

[39] Tutar Y. miRNA and cancer; computational and experimental approaches. Current Pharmaceutical Biotechnology. 2014;**15**(5):429

[40] Garzon R, Marcucci G, Croce CM. Targeting microRNAs in cancer: Rationale, strategies and challenges. Nature Reviews Clinical Oncology. 2010;**48**(Suppl 2):1-6

[41] Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setien F, et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Research. 2007;**67**(4):1424-1429

[42] Baer C, Claus R, Plass C. Genomewide epigenetic regulation of miRNAs in cancer. Cancer Research. 2013;**73**(2):473-477

[43] Hildebrandt MAT, Gu J, Lin J, Ye Y, Tan W, Tamboli P, et al. Hsa-miR-9 methylation status is associated with cancer development and metastatic recurrence in patients with clear cell renal cell carcinoma. Oncogene. 2010;**29**(42):5724-5728

[44] Gibori H, Eliyahu S, Krivitsky A, Ben-Shushan D, Epshtein Y, Tiram G, et al. Amphiphilic nanocarrierinduced modulation of PLK1 and MIR-34a leads to improved therapeutic response in pancreatic cancer. Nature Communications. 2018;**9**(1)

[45] Brueckner B, Stresemann C, Kuner R, Mund C, Musch T, Meister M, et al. The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. Cancer Research. 2007;**67**(4):1419-1423

[46] Wang T, Wang G, Hao D, Liu X, Wang D, Ning N, et al. Aberrant regulation of the LIN28A/LIN28B and let-7 loop in human malignant tumors and its effects on the hallmarks of cancer. Molecular Cancer. 2015;**14**(1):1-13

[47] Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Research. 2005;**65**(14):6029-6033

[48] Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;**25**(4):501-515

[49] Chan YC, Khanna S, Roy S, Sen CK. MiR-200b targets Ets-1 and is down-regulated by hypoxia to induce angiogenic response of endothelial cells. The Journal of Biological Chemistry. 2011;**286**(3):2047-2056

[50] Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz AL, et al. Nutrition and physical activity guidelines for cancer survivors. CA: A Cancer Journal for Cinicians. 2012;**62**(2):242-274

[51] Alibhai SMH, Santa Mina D, Ritvo P, Sabiston C, Krahn M, Tomlinson G, et al. A phase II RCT and economic

analysis of three exercise delivery methods in men with prostate cancer on androgen deprivation therapy. BMC Cancer. 2015

[52] Segal RJ, Reid RD, Courneya KS, Sigal RJ, Kenny GP, Prud'Homme DG, et al. Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer. Journal of Clinical Oncology. 2009;**27**(3):344-351

[53] Newton RU, Taaffe DR, Spry N, Gardiner RA, Levin G, Wall B, et al. A phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate cancer. BMC Cancer. 2009

[54] World Health Organization. Physical Activity [Internet]. 2017. Available from: http://www.who.int/ topics/physical\_activity/en/

[55] Egan B, Zierath JR. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metabolism. 2013;**17**(2):162-184

[56] Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness: Definitions and distinctions for healthrelated research. Public Health Reports. 1985;**100**(2):126-131

[57] Kokkinos P, Myers J, Kokkinos JP, Pittaras A, Narayan P, Manolis A, et al. Exercise capacity and mortality in Black and White men. Circulation. 2008;**117**(5):614-622

[58] Koch LG, Kemi OJ, Qi N, Leng SX, Bijma P, Gilligan LJ, et al. Intrinsic aerobic capacity sets a divide for aging and longevity. Circulation Research. 2011;**109**(10):1162-1172

[59] Wisløff U, Najjar SM, Ellingsen Ø, Haram PM, Swoap S, Al-Share Q, et al. Cardiovascular risk factors emerge after artificial selection for

low aerobic capacity. Science (80- ). 2005;**307**(5708):418-420

[60] Pahor M, Guralnik JM, Ambrosius WT, Blair S, Bonds DE, Church TS, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: The LIFE study randomized clinical trial. JAMA. 2014;**311**(23):2387-2396

[61] Fiuza-Luces C, Garatachea N, Berger NA, Lucia A. Exercise is the real polypill. Physiology. 2013;**28**(5):330-358

[62] Flachenecker P. Autoimmune diseases and rehabilitation. Autoimmunity Reviews. 2012;**11**(3): 219-225

[63] Neilson HK, Friedenreich CM, Brockton NT, Millikan RC. Physical activity and postmenopausal breast cancer: Proposed biologic mechanisms and areas for future research. Cancer Epidemiology, Biomarkers & Prevention. 2009;**18**(1):11-27

[64] Friedenreich CM, Cust AE. Physical activity and breast cancer risk: Impact of timing, type and dose of activity and population subgroup effects. British Journal of Sports Medicine. 2008;**42**(8):636-647

[65] Moore SC, Lee IM, Weiderpass E, Campbell PT, Sampson JN, Kitahara CM, et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Internal Medicine. 2016;**176**(6):816-825

[66] Fernandes T, Magalhães FC, Roque FR, Phillips MI, Oliveira EM. Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: Role of microRNAs-16, -21, and -126. Hypertension. 2012;**59**(2 SUPPL. 1): 513-520

[67] Melo SFS, Fernandes T, Baraúna VG, Matos KC, Santos AAS, Tucci PJF,

**39**

2015;**1**(2):231-237

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

[74] Goh J, Tsai J, Bammler TK, Farin FM, Endicott E, Ladiges WC. Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dose-dependent manner.

[75] Wolff G, Balke JE, Andras IE, Park M, Toborek M. Exercise modulates redox-sensitive small GTPase activity in the brain microvasculature in a model of brain metastasis formation. PLoS One.

[76] Hojman P, Fjelbye J, Zerahn B, Christensen JF, Dethlefsen C, Lonkvist CK, et al. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice. PLoS

[77] Betof AS, Lascola CD, Weitzel D, Landon C, Scarbrough PM, Devi GR, et al. Modulation of murine breast tumor vascularity, hypoxia, and

chemotherapeutic response by exercise. Journal of the National Cancer Institute.

[79] Pedersen L, Idorn M, Olofsson GH, Lauenborg B, Nookaew I, Hansen RH, et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metabolism.

[80] Pigna E, Berardi E, Aulino P, Rizzuto E, Zampieri S, Carraro U, et al. Aerobic exercise and pharmacological treatments counteract cachexia by modulating autophagy in colon cancer. Scientific Reports. 2016;**6**(October

[81] Khori V, Amani Shalamzari S, Isanejad A, Alizadeh AM, Alizadeh S,

[78] Higgins KA, Park D, Lee GY, Curran WJ, Deng X. Exercise-induced lung cancer regression: Mechanistic findings from a mouse model. Cancer.

2014;**120**(21):3302-3310

2016;**23**(3):554-562

2015):26991

One. 2014;**9**(9):e109030

2015;**107**(5):1-5

PLoS One. 2013;**8**(11):e80123

2014;**9**(5):1-8

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

[68] Gomes JLP, Fernandes T, Soci UPR, Silveira AC, Barretti DLM, Negrão CE, et al. Obesity downregulates microRNA-126 inducing capillary rarefaction in skeletal muscle: Effects of aerobic exercise training. Oxidative Medicine and Cellular Longevity.

[69] Fernandes T, Casaes L, Soci U, Silveira A, Gomes J, Barretti D, et al. Exercise training restores the cardiac

preventing microvascular rarefaction in obese Zucker rats. Obesity Facts.

[70] Koelwyn GJ, Jones LW, Moslehi J. Unravelling the causes of reduced peak oxygen consumption in patients with cancer: Complex, timely, and necessary. Journal of American College of Cardiology. 2014;**64**(13):1320-1322

[71] Cramer L, Hildebrandt B, Kung T, Wichmann K, Springer J, Doehner W, et al. Cardiovascular function and predictors of exercise capacity in patients with colorectal cancer. Journal of the American College of Cardiology.

[72] Jones LW, Courneya KS, Mackey JR, Muss HB, Pituskin EN, Scott JM, et al. Cardiopulmonary function and age-related decline across the breast cancer: Survivorship continuum. Journal of Clinical Oncology. 2012;**30**(20):2530-2537

[73] Lakoski SG, Willis BL, Barlow CE, Leonard D, Gao A, Radford NB, et al. Midlife cardiorespiratory fitness, incident cancer, and survival after cancer in men: The Cooper Center Longitudinal Study. JAMA Oncology.

2014;**64**(13):1310-1319

2017;**2017**

2018;**11**(1)

microrna-16 levels

et al. Expression of microRNA-29 and collagen in cardiac muscle after swimming training in myocardialinfarcted rats. Cellular Physiology and Biochemistry. 2014;**33**(3):657-669

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia… DOI: http://dx.doi.org/10.5772/intechopen.84847*

et al. Expression of microRNA-29 and collagen in cardiac muscle after swimming training in myocardialinfarcted rats. Cellular Physiology and Biochemistry. 2014;**33**(3):657-669

*Epigenetics*

Cancer. 2015

2009;**27**(3):344-351

cancer. BMC Cancer. 2009

topics/physical\_activity/en/

[54] World Health Organization. Physical Activity [Internet]. 2017. Available from: http://www.who.int/

[55] Egan B, Zierath JR. Exercise metabolism and the molecular

[56] Caspersen CJ, Powell KE, Christenson GM. Physical activity, exercise, and physical fitness:

1985;**100**(2):126-131

2008;**117**(5):614-622

2011;**109**(10):1162-1172

regulation of skeletal muscle adaptation. Cell Metabolism. 2013;**17**(2):162-184

Definitions and distinctions for healthrelated research. Public Health Reports.

[57] Kokkinos P, Myers J, Kokkinos JP, Pittaras A, Narayan P, Manolis A, et al. Exercise capacity and mortality in Black and White men. Circulation.

[58] Koch LG, Kemi OJ, Qi N, Leng SX, Bijma P, Gilligan LJ, et al. Intrinsic aerobic capacity sets a divide for aging and longevity. Circulation Research.

[59] Wisløff U, Najjar SM, Ellingsen Ø, Haram PM, Swoap S, Al-Share Q, et al. Cardiovascular risk factors emerge after artificial selection for

analysis of three exercise delivery methods in men with prostate cancer on androgen deprivation therapy. BMC low aerobic capacity. Science (80- ).

[60] Pahor M, Guralnik JM, Ambrosius WT, Blair S, Bonds DE, Church TS, et al. Effect of structured physical activity on prevention of major mobility disability in older adults: The LIFE study randomized clinical trial. JAMA.

2005;**307**(5708):418-420

2014;**311**(23):2387-2396

219-225

[61] Fiuza-Luces C, Garatachea N, Berger NA, Lucia A. Exercise is the real polypill. Physiology. 2013;**28**(5):330-358

[62] Flachenecker P. Autoimmune diseases and rehabilitation.

Autoimmunity Reviews. 2012;**11**(3):

[63] Neilson HK, Friedenreich CM, Brockton NT, Millikan RC. Physical activity and postmenopausal breast cancer: Proposed biologic mechanisms

Cancer Epidemiology, Biomarkers &

[64] Friedenreich CM, Cust AE. Physical activity and breast cancer risk: Impact of timing, type and dose of activity and population subgroup effects. British Journal of Sports Medicine.

[65] Moore SC, Lee IM, Weiderpass E, Campbell PT, Sampson JN, Kitahara CM, et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Internal Medicine. 2016;**176**(6):816-825

[66] Fernandes T, Magalhães FC, Roque FR, Phillips MI, Oliveira EM. Exercise training prevents the microvascular rarefaction in hypertension balancing angiogenic and apoptotic factors: Role of microRNAs-16, -21, and -126. Hypertension. 2012;**59**(2 SUPPL. 1):

[67] Melo SFS, Fernandes T, Baraúna VG, Matos KC, Santos AAS, Tucci PJF,

and areas for future research.

Prevention. 2009;**18**(1):11-27

2008;**42**(8):636-647

513-520

[52] Segal RJ, Reid RD, Courneya KS, Sigal RJ, Kenny GP, Prud'Homme DG, et al. Randomized controlled trial of resistance or aerobic exercise in men receiving radiation therapy for prostate cancer. Journal of Clinical Oncology.

[53] Newton RU, Taaffe DR, Spry N, Gardiner RA, Levin G, Wall B, et al. A phase III clinical trial of exercise modalities on treatment side-effects in men receiving therapy for prostate

**38**

[68] Gomes JLP, Fernandes T, Soci UPR, Silveira AC, Barretti DLM, Negrão CE, et al. Obesity downregulates microRNA-126 inducing capillary rarefaction in skeletal muscle: Effects of aerobic exercise training. Oxidative Medicine and Cellular Longevity. 2017;**2017**

[69] Fernandes T, Casaes L, Soci U, Silveira A, Gomes J, Barretti D, et al. Exercise training restores the cardiac microrna-16 levels preventing microvascular rarefaction in obese Zucker rats. Obesity Facts. 2018;**11**(1)

[70] Koelwyn GJ, Jones LW, Moslehi J. Unravelling the causes of reduced peak oxygen consumption in patients with cancer: Complex, timely, and necessary. Journal of American College of Cardiology. 2014;**64**(13):1320-1322

[71] Cramer L, Hildebrandt B, Kung T, Wichmann K, Springer J, Doehner W, et al. Cardiovascular function and predictors of exercise capacity in patients with colorectal cancer. Journal of the American College of Cardiology. 2014;**64**(13):1310-1319

[72] Jones LW, Courneya KS, Mackey JR, Muss HB, Pituskin EN, Scott JM, et al. Cardiopulmonary function and age-related decline across the breast cancer: Survivorship continuum. Journal of Clinical Oncology. 2012;**30**(20):2530-2537

[73] Lakoski SG, Willis BL, Barlow CE, Leonard D, Gao A, Radford NB, et al. Midlife cardiorespiratory fitness, incident cancer, and survival after cancer in men: The Cooper Center Longitudinal Study. JAMA Oncology. 2015;**1**(2):231-237

[74] Goh J, Tsai J, Bammler TK, Farin FM, Endicott E, Ladiges WC. Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dose-dependent manner. PLoS One. 2013;**8**(11):e80123

[75] Wolff G, Balke JE, Andras IE, Park M, Toborek M. Exercise modulates redox-sensitive small GTPase activity in the brain microvasculature in a model of brain metastasis formation. PLoS One. 2014;**9**(5):1-8

[76] Hojman P, Fjelbye J, Zerahn B, Christensen JF, Dethlefsen C, Lonkvist CK, et al. Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice. PLoS One. 2014;**9**(9):e109030

[77] Betof AS, Lascola CD, Weitzel D, Landon C, Scarbrough PM, Devi GR, et al. Modulation of murine breast tumor vascularity, hypoxia, and chemotherapeutic response by exercise. Journal of the National Cancer Institute. 2015;**107**(5):1-5

[78] Higgins KA, Park D, Lee GY, Curran WJ, Deng X. Exercise-induced lung cancer regression: Mechanistic findings from a mouse model. Cancer. 2014;**120**(21):3302-3310

[79] Pedersen L, Idorn M, Olofsson GH, Lauenborg B, Nookaew I, Hansen RH, et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metabolism. 2016;**23**(3):554-562

[80] Pigna E, Berardi E, Aulino P, Rizzuto E, Zampieri S, Carraro U, et al. Aerobic exercise and pharmacological treatments counteract cachexia by modulating autophagy in colon cancer. Scientific Reports. 2016;**6**(October 2015):26991

[81] Khori V, Amani Shalamzari S, Isanejad A, Alizadeh AM, Alizadeh S, Khodayari S, et al. Effects of exercise training together with tamoxifen in reducing mammary tumor burden in mice: Possible underlying pathway of MIR-21. European Journal of Pharmacology. 2015;**765**:179-187

[82] Isanejad A, Alizadeh AM, Amani Shalamzari S, Khodayari H, Khodayari S, Khori V, et al. MicroRNA-206, let-7a and microRNA-21 pathways involved in the anti-angiogenesis effects of the interval exercise training and hormone therapy in breast cancer. Life Sciences. 2016;**151**:30-40

[83] Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: An international consensus. The Lancet Oncology. 2011;**12**(5):489-495

[84] Argilés JM, Busquets S, Stemmler B, López-Soriano FJ. Cancer cachexia: Understanding the molecular basis. Nature Reviews. Cancer. 2014;**14**(11):754-762

[85] Tisdale MJ. Mechanisms of cancer cachexia. Physiological Reviews. 2009;**89**(2):381-410

[86] Acunzo M, Croce CM. MicroRNA in cancer and cachexia—A mini-review. The Journal of Infectious Diseases. 2015;**212**(Suppl 1):S74-S77

[87] Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. Mechanisms regulating skeletal muscle growth and atrophy. The FEBS Journal. 2013;**280**(17):4294-4314

[88] Fearon KCH, Glass DJ, Guttridge DC. Cancer cachexia: Mediators, signaling, and metabolic pathways. Cell Metabolism. 2012;**16**(2):153-166

[89] Segatto M, Fittipaldi R, Pin F, Sartori R, Ko KD, Zare H, et al. counteracts cancer cachexia and prolongs survival. Nature Communications:1-15

[90] Samant SA, Pillai VB, Gupta MP. Cellular mechanisms promoting cachexia and how they are opposed by sirtuins. Canadian Journal of Physiology and Pharmacology. 2018:1-38

[91] Fernandez-Zapico ME, Fernandez-Barrena MG, Marks DL. Discovering and targeting the epigenetic pathways to treat muscle loss: Working toward a paradigm shift in cancer therapeutics. Current Opinion in Supportive and Palliative Care. 2014:319-320

[92] Sharples AP, Polydorou I, Hughes DC, Owens DJ, Hughes TM, Stewart CE. Skeletal muscle cells possess a 'memory' of acute early life TNF-α exposure: Role of epigenetic adaptation. Biogerontology. 2016;**17**(3):603-617

[93] Dai Y, Wang YM, Zhang WR, Liu XF, Li X, Ding X, et al. The role of microRNA-1 and microRNA-206 in the proliferation and differentiation of bovine skeletal muscle satellite cells. In Vitro Cellular & Developmental Biology: Animal. 2016;**52**(1):27-34

[94] Siracusa J, Koulmann N, Banzet S. Circulating myomiRs: A new class of biomarkers to monitor skeletal muscle in physiology and medicine. Journal of Cachexia, Sarcopenia and Muscle. November;**2018**:20-27

[95] Lee DE, Brown JL, Rosa-Caldwell ME, Blackwell TA, Perry RA, Brown LA, et al. Cancer cachexia-induced muscle atrophy: Evidence for alterations in microRNAs important for muscle size. Physiological Genomics. 2018;**182**(16):253-260

[96] Narasimhan A, Ghosh S, Stretch C, Greiner R, Bathe OF, Baracos V, et al. Small RNAome profiling from human skeletal muscle: Novel miRNAs and their targets associated with cancer cachexia. January. 2017:405-416

[97] Kulyté A, Lorente-Cebrián S, Gao H, Mejhert N, Agustsson T, Arner P, et al.

**41**

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia…*

[105] Improta Caria AC, Nonaka CKV, Pereira CS, Soares MBP, Macambira SG, Souza BSF. Exercise training-induced changes in microRNAs: Beneficial regulatory effects in hypertension, type 2 diabetes, and obesity. International Journal of Molecular Sciences. 2018

*DOI: http://dx.doi.org/10.5772/intechopen.84847*

MicroRNA profiling links miR-378 to enhanced adipocyte lipolysis in human cancer cachexia. American Journal of Physiology. Endocrinology and

[98] Okugawa Y, Yao LI, Toiyama Y, Yamamoto A, Shigemori T, Yin C, et al. Prognostic impact of sarcopenia and its correlation with circulating miR-21 in colorectal cancer patients. Oncology

Metabolism. 2018:267-274

Reports. 2018:1555-1564

2014;**111**(12):4525-4529

2016;**65**(5):685-698

[99] He WA, Calore F, Londhe P, Canella A, Guttridge DC, Croce CM. Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7. Proceedings of the National Academy of Sciences of the United States of America.

[100] Oh S, Elam ML, Jo E, Arjmandi BH. Aerobic and resistance training dependent skeletal muscle plasticity in the colon-26 murine model of cancer cachexia. Metabolism.

[101] Baggish AL, Park J, Min P-K, Isaacs S, Parker BA, Thompson PD, et al. Rapid upregulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise. Journal of Applied Physiology. 2014;**116**(5):522-531

[102] Yu H, Lu Y, Li Z, Wang Q. microRNA-133: Expression, function and therapeutic potential in muscle diseases and cancer. Current Drug Targets. 2014;**15**(9):817-828

[103] Safdar A, Saleem A, Tarnopolsky MA. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nature Reviews. Endocrinology. 2016;**12**(9):504-517

[104] Staszel T, Zapała B, Polus A, Sadakierska-Chudy A, Kieć-Wilk B, Stȩpień E, et al. Role of microRNAs in endothelial cell pathophysiology. Polskie Archiwum Medycyny Wewnętrznej.

2011;**121**(10):361-367

*A Landscape of Epigenetic Regulation by MicroRNAs to the Hallmarks of Cancer and Cachexia… DOI: http://dx.doi.org/10.5772/intechopen.84847*

MicroRNA profiling links miR-378 to enhanced adipocyte lipolysis in human cancer cachexia. American Journal of Physiology. Endocrinology and Metabolism. 2018:267-274

*Epigenetics*

2016;**151**:30-40

2011;**12**(5):489-495

2014;**14**(11):754-762

2009;**89**(2):381-410

2015;**212**(Suppl 1):S74-S77

Khodayari S, et al. Effects of exercise training together with tamoxifen in reducing mammary tumor burden in mice: Possible underlying pathway of MIR-21. European Journal of Pharmacology. 2015;**765**:179-187

[90] Samant SA, Pillai VB, Gupta MP. Cellular mechanisms promoting cachexia and how they are opposed by sirtuins. Canadian Journal of Physiology

and Pharmacology. 2018:1-38

[91] Fernandez-Zapico ME, Fernandez-Barrena MG, Marks DL. Discovering and targeting the epigenetic pathways to treat muscle loss: Working toward a paradigm shift in cancer therapeutics. Current Opinion in Supportive and Palliative Care. 2014:319-320

[92] Sharples AP, Polydorou I, Hughes DC, Owens DJ, Hughes TM, Stewart CE. Skeletal muscle cells possess a 'memory' of acute early life TNF-α exposure: Role of epigenetic adaptation. Biogerontology. 2016;**17**(3):603-617

[93] Dai Y, Wang YM, Zhang WR, Liu XF, Li X, Ding X, et al. The role of microRNA-1 and microRNA-206 in the proliferation and differentiation of bovine skeletal muscle satellite cells. In Vitro Cellular & Developmental Biology: Animal. 2016;**52**(1):27-34

[94] Siracusa J, Koulmann N, Banzet S. Circulating myomiRs: A new class of biomarkers to monitor skeletal muscle in physiology and medicine. Journal of Cachexia, Sarcopenia and Muscle.

[95] Lee DE, Brown JL, Rosa-Caldwell ME, Blackwell TA, Perry RA, Brown LA, et al. Cancer cachexia-induced muscle atrophy: Evidence for alterations in microRNAs important for muscle size. Physiological Genomics.

[96] Narasimhan A, Ghosh S, Stretch C, Greiner R, Bathe OF, Baracos V, et al. Small RNAome profiling from human skeletal muscle: Novel miRNAs and their targets associated with cancer cachexia. January. 2017:405-416

[97] Kulyté A, Lorente-Cebrián S, Gao H, Mejhert N, Agustsson T, Arner P, et al.

November;**2018**:20-27

2018;**182**(16):253-260

[82] Isanejad A, Alizadeh AM, Amani Shalamzari S, Khodayari H, Khodayari S, Khori V, et al. MicroRNA-206, let-7a and microRNA-21 pathways involved in the anti-angiogenesis effects of the interval exercise training and hormone therapy in breast cancer. Life Sciences.

[83] Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: An international consensus. The Lancet Oncology.

[84] Argilés JM, Busquets S, Stemmler B, López-Soriano FJ. Cancer cachexia:

[85] Tisdale MJ. Mechanisms of cancer cachexia. Physiological Reviews.

[86] Acunzo M, Croce CM. MicroRNA in cancer and cachexia—A mini-review. The Journal of Infectious Diseases.

[87] Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. Mechanisms regulating skeletal muscle growth and atrophy. The FEBS Journal. 2013;**280**(17):4294-4314

[88] Fearon KCH, Glass DJ, Guttridge DC. Cancer cachexia: Mediators, signaling, and metabolic pathways. Cell

Metabolism. 2012;**16**(2):153-166

[89] Segatto M, Fittipaldi R, Pin F, Sartori R, Ko KD, Zare H, et al. counteracts cancer cachexia and prolongs survival. Nature

Communications:1-15

Understanding the molecular basis. Nature Reviews. Cancer.

**40**

[98] Okugawa Y, Yao LI, Toiyama Y, Yamamoto A, Shigemori T, Yin C, et al. Prognostic impact of sarcopenia and its correlation with circulating miR-21 in colorectal cancer patients. Oncology Reports. 2018:1555-1564

[99] He WA, Calore F, Londhe P, Canella A, Guttridge DC, Croce CM. Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7. Proceedings of the National Academy of Sciences of the United States of America. 2014;**111**(12):4525-4529

[100] Oh S, Elam ML, Jo E, Arjmandi BH. Aerobic and resistance training dependent skeletal muscle plasticity in the colon-26 murine model of cancer cachexia. Metabolism. 2016;**65**(5):685-698

[101] Baggish AL, Park J, Min P-K, Isaacs S, Parker BA, Thompson PD, et al. Rapid upregulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise. Journal of Applied Physiology. 2014;**116**(5):522-531

[102] Yu H, Lu Y, Li Z, Wang Q. microRNA-133: Expression, function and therapeutic potential in muscle diseases and cancer. Current Drug Targets. 2014;**15**(9):817-828

[103] Safdar A, Saleem A, Tarnopolsky MA. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nature Reviews. Endocrinology. 2016;**12**(9):504-517

[104] Staszel T, Zapała B, Polus A, Sadakierska-Chudy A, Kieć-Wilk B, Stȩpień E, et al. Role of microRNAs in endothelial cell pathophysiology. Polskie Archiwum Medycyny Wewnętrznej. 2011;**121**(10):361-367

[105] Improta Caria AC, Nonaka CKV, Pereira CS, Soares MBP, Macambira SG, Souza BSF. Exercise training-induced changes in microRNAs: Beneficial regulatory effects in hypertension, type 2 diabetes, and obesity. International Journal of Molecular Sciences. 2018

**43**

**Chapter 4**

**Abstract**

breast cancer, biomarkers

**1. Introduction**

Consequences of Artificial Light

*Abraham Haim, Sinam Boynao and Abed Elsalam Zubidat*

Epigenetics is an important tool for understanding the relation between environmental exposures and cellular functions, including metabolic and proliferative responses. At our research center, we have devolved a mouse model for characterizing the relation between exposure to artificial light at night (ALAN) and both global DNA methylation (GDM) and breast cancer. Generally, the model describes a close association between ALAN and cancer responses. Cancer responses are eminent at all light spectra, with the prevalent manifestation at the shorter end of the visible spectrum. ALAN-induced pineal melatonin suppression is the principal candidate mechanism mediating the environmental exposure at the molecular level by eliciting aberrant GDM modifications. The carcinogenic potential of ALAN can be ameliorated in mice by exogenous melatonin treatment. In contrast to BALB/c mice, humans are diurnal species, and thus, it is of great interest to evaluate the ALAN-melatonin-GDM nexus also in a diurnal mouse model. The fat sand rat (*Psammomys obesus*) provides an appropriate model as its responses to photoperiod are comparable to humans. Interestingly, melatonin and thyroxin have opposite effects on GDM levels in *P. obesus*. Melatonin, GDM levels, and even thyroxin may be utilized as novel biomarkers for

detection, staging, therapy, and prevention of breast cancer progression.

**Keywords:** melatonin, thyroxin, light-at-night, global DNA methylation, diurnal species,

Since the invention of electrical light in 1879 by Thomas Alva Edison, artificial light at night (ALAN) has become a definitive feature of human development with accelerated increase concurrent with urbanization and industrialization. The light emitted from the original bulb of Edison known as incandescent bulb was weak, with a dominant long wavelength emission above 560 nm. Most of the incandescent electrical energy is dissipated as heat energy, thus making this type of illumination energetically inefficient. Therefore, new illumination technologies were developed, in order to discover efficient bulbs that transfer most of the electrical energy into light. White fluorescent and light-emitting diodes (LED) are examples of energy efficient bulbs developed to decrease carbon dioxide production from electric power plants, thus lessening the greenhouse effect. One of the adverse outcomes of using efficient

at Night: The Linkage between

Chasing Darkness Away and

Epigenetic Modifications

## **Chapter 4**
