**5.2 Colorectal cancer**

Colorectal cancer is the third most common cancer around the world. The incidence rate is increased up to 6% [66]. Survival rate can increase to 90%, if it is diagnosed at an early stage. Survival rate is inversely proportional to the stage of cancer [67].

In a study, the cluster of miR-17/miR-92 (chromosomal region 13q31.1 with miR-20a as one of its members). The region encompassing this cluster is under the regulation of the oncogenic Myc transcriptional factor and TGF-β [68, 69]. Overexpression converts a benign tumor to colorectal cancer [70].

Mir-20 acts as a potential colorectal cancer cell biomarker [71]. Induction of miR-20-mediated EMT is a critical factor contributing to the increases in tumor cell migration, metastasis, E-cadherin downregulation, and upregulation of matrix metalloproteinases (**Figure 5**) [72, 73]. This microRNA can cause a delay in TGF-βmediated G1/S transition. However, cell cycle progression occurs due to an inactivating mutation in this pathway [74]. Normal TGF-β-mediated signaling can be a cytostatic response and inhibit tumorigenicity in colorectal cancer cells [75].

**Figure 5.** *MicroRNA and colorectal cancer.*

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

miR-20 may be degraded by a bacterial strain that is dominant in the lumen of the bowel of colorectal patients. Hence, expression of miR-20a is reduced in patients having colorectal adenoma [76–78].

In another study, miR-34a modulates EMT and MET processes. There is methylation in CpG islands (cancer specific), and these are repressed by *IL-6/STAT3* pathway which is mediated by *interleukin-6 receptors* (*IL6R)* and *inactivation of TP53*. This results in downregulation of miR-34a [79]. miR-34a inhibits SIRT and activates *TP53.* A positive feedback loop has been suggested between miR-34a (**Table 3**) and TP53 [81]. In many cancers, TP53-inducible microRNA is miR-34a [82].

In another study, miR-200 is downregulated in primary colorectal cancer (invasive stage) correlatable with the disruption of the basement membrane [83]. The miR-200 family consists of five members and is encoded in two clusters. One cluster is present on chromosome 1 and encodes for miR-200a, miR-200b, miR-200c, and miR-141. The other cluster is present on chromosome 12 and encodes for miR-141. The potential target of miR-200 family is ZEB1/ZEB2 which is a repressor of CDH1 (**Table 4**). Expression of all members of this family can be repressed following methylation of CpG islands in the regulatory region of their genes [84, 85]. Strong expression of miR-200 results in metastatic colorectal cancer [83]. Another study shows that miR-155 and miR-21 are overexpressed in colorectal cancer [86]. In another study involving colorectal cancer patients, the expression of miR-195 and miR-497 is reduced [87].

### **5.3 Cervical cancer**

is amplified in breast cancer and aids in the sorting of epidermal growth factor receptor (EGFR) [62, 63]. For the metastasis or migration of cancer, the cell critical factor is RCP which mediates this effect via cell surface integrin alpha-5-beta-1 demonstrating that Rab11a is a protein that is involved in the metastatic or invasive

Colorectal cancer is the third most common cancer around the world. The incidence rate is increased up to 6% [66]. Survival rate can increase to 90%, if it is diagnosed at an early stage. Survival rate is inversely proportional to the stage of

In a study, the cluster of miR-17/miR-92 (chromosomal region 13q31.1 with miR-20a as one of its members). The region encompassing this cluster is under the

Mir-20 acts as a potential colorectal cancer cell biomarker [71]. Induction of miR-20-mediated EMT is a critical factor contributing to the increases in tumor cell migration, metastasis, E-cadherin downregulation, and upregulation of matrix metalloproteinases (**Figure 5**) [72, 73]. This microRNA can cause a delay in TGF-β-

inactivating mutation in this pathway [74]. Normal TGF-β-mediated signaling can be a cytostatic response and inhibit tumorigenicity in colorectal cancer cells [75].

regulation of the oncogenic Myc transcriptional factor and TGF-β [68, 69].

mediated G1/S transition. However, cell cycle progression occurs due to an

Overexpression converts a benign tumor to colorectal cancer [70].

phenotype of breast cancer [64, 65].

**5.2 Colorectal cancer**

*MicroRNA and breast cancer.*

*Current Cancer Treatment*

cancer [67].

**Figure 5.**

**8**

*MicroRNA and colorectal cancer.*

**Figure 4.**

Cervical cancer is the most common cause of death among women in the developing countries [88, 89]. Cervical cancer can cause the death of 270,000 women per year [90]. Human papillomavirus (HPV) is the causative agent, with the E6 and E7 proteins targeting p53 and pRb, respectively [91].


#### **Table 3.**

*MicroRNAs suppressing the colorectal cancer [80].*


**Table 4.** *MicroRNAs promoting the colorectal cancer [80].*


#### **Table 5.**

*AmiRNA involved in cervical cancer.*

Several miRNAs are upregulated and downregulated during cervical cancer (**Table 5**). miR-135b is a biomarker for cervical cancer. Suppression of this biomarker results in the inhibition of cell growth.

Downregulation of miR-135b results in the percentage of G1 cells with a concomitant decrease in those in the S phase. The expression of cyclin-dependent kinases (p27 and p21) is increased and that of cyclin D1 is decreased. Cyclin D1 (nuclear protein) is responsible for the regulation of cells (proliferating) that are at the G1 phase of the cell cycle [72, 73].

There seems to be an inverse relationship between miR-135b and FOXO1 protein. When FOXO1 protein is downregulated, cervical cancer is promoted. When FOXO1 protein is expressed, then there is an increase in the p27 and p21 expression with a decrease in cyclin D1 level and cell cycle is arrested [95, 96]. So, when miR-135 is downregulated, FOXO1 is upregulated with the resultant inhibition of cell growth (**Figure 6**).

In cervical cancer, miR-196a is upregulated and its targets are p27Kip and FOXO1. It promotes the transition of cells from G1 phase to S phase, enhances the cellular proliferation by involving the PI3K/Akt pathway, and is involved in tumorigenesis [97].

1gene. This AP-1 binds to a specific site on the promoter of miR-21 and as a result miR-21 gene is transcribed [99], thereby providing a plausible mechanism for a

**Sr. no. MicroRNAs Potential targets Function Ref.**

Increases in cell proliferation and

Cell growth followed by migration

Enhances the expression of genes associated with cell proliferation, metastasis, as well as those involved in the antiapoptosis effect

in apoptosis (miR-10a, miR-106b, miR-21, miR-135b, miR-141, miR146, miR-148a, miR-214, and

Migration, colony formation, and

Inhibition of apoptosis and uncontrolled cell proliferation

cervical cancer

Aberrations in cell proliferation and differentiation—cell transformation

Suppressing the progression of

[97]

[91]

[91]

[91]

[91]

tumorigenesis

and invasion

miR-886-5p)

invasion

UTR of p27Kip and

4 miR-886-5p Negatively regulates the Bax gene Dysregulation of the gene involved

UTR of mRNA of

FOXO1 and inhibits their

expression of close homolog of L1 (CHL1) transmembrane protein type 1—a cell-adhesion protein

Cdc25, TPM1 and RECK, and PTEN and PDCD4

TNKS2 results in enhanced

translation

2 miR-10a Has an inverse relation with the

3 miR-21 Negatively regulates p53 and

5 miR-20a TNKS2 oncogene is upregulated (by binding at 3<sup>0</sup>

translation)

It was reported that miR-886-5p targets and negatively regulates Bax gene expression via inhibition of translation, and hence, this form of control may be significant for the development of cervical cancer. When there is a death signal, the proapoptotic protein coded by Bax gene is inserted into the outer membrane of mitochondria. As a result, cytochrome C is released, and the initiator caspase-9 is

Liver cancer is rising very rapidly globally with aflatoxins also contributing to its etiology. Specific miRNA may be expressed in the case of liver cancer. One of the

subsequently activated with the initiation of apoptosis (**Table 7**) [91].

**Sr. no. MicroRNAs Potential target Function**

as well as inhibits the translation of SP-1

1 miR-143 Target k-Ras, Bcl-2 and Macc1, specifically downregulation of Bcl-2

2 miR-129-5p Downregulates HPV18 E5 and E7 expression

transcriptional factor

3 miR-34a Cyclin E2 and D1, CDK6, E2F3, CDK4, E2F1, E2F5, P18, Bcl-2, and SIRT1

positive feedback loop.

*MicroRNAs activating the cervical cancer.*

**Table 6.**

1 miR-196a Binds to the 3<sup>0</sup>

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

**5.4 Liver cancer**

**Table 7.**

**11**

*MicroRNAs suppressing cervical cancer [91].*

In one study, miR-10a is overexpressed in cervical cancer (Long et al., 2012; [28]). The target of miR-10a is transmembrane protein type 1 close homolog of L1 (CHL1) that is downregulated. A decrease in CHL1 protein dysregulates PAK and MAPK pathways resulting in increases in cell growth followed by migration and invasion [98].

In another study, miR-21 is upregulated in cervical cancer, and it is located at the 17q23.21 locus (**Table 6**). The pri-miR-21 is transcribed by the intronic region of TMEM49 (protein-coding gene). This miRNA targets the p53 and Cdc25 (regulators of the expression of genes), TPM1 and RECK (suppressing the metastasis), and PTEN and PDCD4 (inducing the apoptosis of metastasized cell). Hence, decreases in this miRNA can result in the PDCD4 gene providing signals for the activation of the RAS pathway. This activation, in turn, activates the transcription factor AP-

**Figure 6.** *MicroRNA and cervical cancer.*

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*


**Table 6.**

Several miRNAs are upregulated and downregulated during cervical cancer (**Table 5**). miR-135b is a biomarker for cervical cancer. Suppression of this bio-

miR-491-5p Downregulated; suppress cervical cancer by telomerase reverse transcriptase and

miR-142-3p Inhibit the proliferation of cell Frizzled\_7 receptor (FZD7) [93] miR-142-3p Inhibit the growth of cell via downregulation of its FOXM1 target [94]

**Function Ref.**

[92]

Downregulation of miR-135b results in the percentage of G1 cells with a concomitant decrease in those in the S phase. The expression of cyclin-dependent kinases (p27 and p21) is increased and that of cyclin D1 is decreased. Cyclin D1 (nuclear protein) is responsible for the regulation of cells (proliferating) that are at

There seems to be an inverse relationship between miR-135b and FOXO1 protein. When FOXO1 protein is downregulated, cervical cancer is promoted. When FOXO1 protein is expressed, then there is an increase in the p27 and p21 expression with a decrease in cyclin D1 level and cell cycle is arrested [95, 96]. So, when miR-135 is downregulated, FOXO1 is upregulated with the resultant inhibition of cell

In cervical cancer, miR-196a is upregulated and its targets are p27Kip and FOXO1. It promotes the transition of cells from G1 phase to S phase, enhances the cellular proliferation by involving the PI3K/Akt pathway, and is involved in

In one study, miR-10a is overexpressed in cervical cancer (Long et al., 2012; [28]). The target of miR-10a is transmembrane protein type 1 close homolog of L1 (CHL1) that is downregulated. A decrease in CHL1 protein dysregulates PAK and MAPK pathways resulting in increases in cell growth followed by migration and

In another study, miR-21 is upregulated in cervical cancer, and it is located at the 17q23.21 locus (**Table 6**). The pri-miR-21 is transcribed by the intronic region of TMEM49 (protein-coding gene). This miRNA targets the p53 and Cdc25 (regulators of the expression of genes), TPM1 and RECK (suppressing the metastasis), and PTEN and PDCD4 (inducing the apoptosis of metastasized cell). Hence, decreases in this miRNA can result in the PDCD4 gene providing signals for the activation of the RAS pathway. This activation, in turn, activates the transcription factor AP-

marker results in the inhibition of cell growth.

regulate the PI3K/AKT pathway

the G1 phase of the cell cycle [72, 73].

*AmiRNA involved in cervical cancer.*

growth (**Figure 6**).

**Type of miRNA**

*Current Cancer Treatment*

**Table 5.**

tumorigenesis [97].

invasion [98].

**Figure 6.**

**10**

*MicroRNA and cervical cancer.*

*MicroRNAs activating the cervical cancer.*

1gene. This AP-1 binds to a specific site on the promoter of miR-21 and as a result miR-21 gene is transcribed [99], thereby providing a plausible mechanism for a positive feedback loop.

It was reported that miR-886-5p targets and negatively regulates Bax gene expression via inhibition of translation, and hence, this form of control may be significant for the development of cervical cancer. When there is a death signal, the proapoptotic protein coded by Bax gene is inserted into the outer membrane of mitochondria. As a result, cytochrome C is released, and the initiator caspase-9 is subsequently activated with the initiation of apoptosis (**Table 7**) [91].

#### **5.4 Liver cancer**

Liver cancer is rising very rapidly globally with aflatoxins also contributing to its etiology. Specific miRNA may be expressed in the case of liver cancer. One of the


**Table 7.** *MicroRNAs suppressing cervical cancer [91].*

zinc finger protein was originally a transcriptional factor and binds to the promoter region of the human papillomavirus (HPV). This protein mediates the regulation of PI3K/Akt pathway and causes the inhibition of cell growth via the induction of caspase-3 and the promotion of apoptosis. The expression of miR-525-3p enhances

**Sr. no. MicroRNAs Potential targets Function Ref.**

2 miR-525-3p Downregulates ZNF395 Enhances cell growth and prevent apoptosis [104]

Suppress the tumor suppressor [103]

In countries in the West, prostate cancer is a more prevalent form of cancer among males with an increasing incidence rate [105]. Prostate cancer is the result of undesirable genomic alteration [106, 107]. CD9 is inactivated during prostate can-

In the prostate cancer, serum level of miR-141 is elevated [109]. So it acts as the biomarker of prostate cancer. In the progression or repression of prostate cancer, miR-141 function is understood poorly [110]. One other study is done by Waltering et al. in which miR-141 is castrated and results in upregulation and activation (**Figure 8**). This causes the LNCaP cell growth to increase. This miRNA is also involved in the regulation of signaling of the androgen. This androgen has a crucial

role in the growth of prostate cancer (castration-resistant and androgen-

dependent). So it may be involved in the progression of prostate cancer [111, 112]. In a study involving prostate cancer, miR-888 was found to be upregulated. Its target is the tumor suppressors SMAD4 and RBL1. Binding of this miRNA to the

UTR causes their downregulation. RBL1 is the member of the RB (retinoblastoma) family and blocks the progression of cells at the G1-S phase following its binding and inhibition of the transcription factor E2F. SMAD4 protein binds to SMAD receptors and transduces the signal initiated by TGF-β/BMP ligands in order to

In another study, there is the downregulation of miR-23a, b (**Table 10**). There is upregulation of the-Myc gene which causes the repression of these miRNAs at the transcriptional level. Mitochondrial glutaminase protein is expressed in the prostate

cell growth and prevention of apoptosis [104].

1 miR-9 Influences the PPARA/

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

*MicroRNAs activating the liver cancer.*

CDH1pathway

cer and may cause its progression [108].

regulate differentiation and cell growth [113].

**5.5 Prostate cancer**

**Table 9.**

30

**Figure 8.**

**13**

*miRNA and prostate cancer.*

**Figure 7.** *MicroRNA and liver cancer.*

miRNA biomarkers in liver cancer is miR-26a. Its expression is reduced in liver cancer unlike normal hepatic cells, where its expression level is increased [100].

miR-26a and miR-34a cause an increased number of cells in the G1 phase of the cell cycle, while there is a decrease in the cells in the S phase of the cell cycle. miR-26 causes cell cycle arrest at the G1 phase [84]. In the 3<sup>0</sup> UTR region of cyclins E2 and D2, there is a conserved binding site for miR-26a. miR-26a binds to these binding sites and represses the expression of both cyclins (**Figure 7**). miR-26 causes the induction of apoptosis in the tumor cells and suppresses hepatic cancer [101].

Kim et al. studied the expression of miR-31 in liver cancer (**Table 8**). The main target of miR-31 is CDK2 protein and HDAC2, with these proteins suppressed in the livers of normal individuals. There is an enhanced expression of CDK2 protein and HDAC2 in liver cancer. When HDAC2 is suppressed, p21WAF1/Cip1 and p16INK4A are activated, and positive regulators of the cell cycle (cyclin D1, CDK2, and CDK4) are suppressed simultaneously [102].

In another study, the expression of miR-9 enhances the formation of tumor spheres in the liver. The direct target of the miR-9 is PPARA and CDH1 genes and regulates them via binding to the 3<sup>0</sup> UTR region of these genes. Upregulation of miR-9 enhances the level of vimentin (mesenchymal marker) and deregulates the CDH1 (**Table 9**). The transcriptional factor PPARA has been implicated in the metabolic homeostasis of the liver by regulating the nuclear factor-4 alpha (hepatocyte HNF4A) gene, which is a tumor suppressor. In liver cancer, miR-9 suppresses the CDH1 and also suppresses the PPARA at their mRNA level by binding to the 3<sup>0</sup> UTR of these genes [103].

In one study, there is overexpression of miR-525-3p in liver cancer, and its potential target is a zinc finger protein (Krüppel C2H2 type family) ZNF395. This


**Table 8.** *MicroRNAs suppressing the liver cancer.*


**Table 9.**

miRNA biomarkers in liver cancer is miR-26a. Its expression is reduced in

causes cell cycle arrest at the G1 phase [84]. In the 3<sup>0</sup>

suppressed simultaneously [102].

regulates them via binding to the 3<sup>0</sup>

**Sr. no. MicroRNAs Potential**

1 miR-26a Cyclin E2 and

2 miR-31 CDK2 protein

*MicroRNAs suppressing the liver cancer.*

**targets**

and HDAC2

D2

of these genes [103].

**Table 8.**

**12**

**Figure 7.**

*MicroRNA and liver cancer.*

*Current Cancer Treatment*

liver cancer unlike normal hepatic cells, where its expression level is increased [100]. miR-26a and miR-34a cause an increased number of cells in the G1 phase of the cell cycle, while there is a decrease in the cells in the S phase of the cell cycle. miR-26

D2, there is a conserved binding site for miR-26a. miR-26a binds to these binding sites and represses the expression of both cyclins (**Figure 7**). miR-26 causes the induction of apoptosis in the tumor cells and suppresses hepatic cancer [101].

Kim et al. studied the expression of miR-31 in liver cancer (**Table 8**). The main target of miR-31 is CDK2 protein and HDAC2, with these proteins suppressed in the livers of normal individuals. There is an enhanced expression of CDK2 protein and HDAC2 in liver cancer. When HDAC2 is suppressed, p21WAF1/Cip1 and p16INK4A are activated, and positive regulators of the cell cycle (cyclin D1, CDK2, and CDK4) are

In another study, the expression of miR-9 enhances the formation of tumor spheres in the liver. The direct target of the miR-9 is PPARA and CDH1 genes and

9 enhances the level of vimentin (mesenchymal marker) and deregulates the CDH1 (**Table 9**). The transcriptional factor PPARA has been implicated in the metabolic homeostasis of the liver by regulating the nuclear factor-4 alpha (hepatocyte HNF4A) gene, which is a tumor suppressor. In liver cancer, miR-9 suppresses the CDH1 and also suppresses the PPARA at their mRNA level by binding to the 3<sup>0</sup>

In one study, there is overexpression of miR-525-3p in liver cancer, and its potential target is a zinc finger protein (Krüppel C2H2 type family) ZNF395. This

processes

UTR region of cyclins E2 and

UTR

[102]

UTR region of these genes. Upregulation of miR-

**Function Ref.**

The arrest of the cell cycle at G1 phase [84]

Suppress the positive regulators of cell cycle and promote those proteins involved in EMT-related *MicroRNAs activating the liver cancer.*

zinc finger protein was originally a transcriptional factor and binds to the promoter region of the human papillomavirus (HPV). This protein mediates the regulation of PI3K/Akt pathway and causes the inhibition of cell growth via the induction of caspase-3 and the promotion of apoptosis. The expression of miR-525-3p enhances cell growth and prevention of apoptosis [104].

#### **5.5 Prostate cancer**

In countries in the West, prostate cancer is a more prevalent form of cancer among males with an increasing incidence rate [105]. Prostate cancer is the result of undesirable genomic alteration [106, 107]. CD9 is inactivated during prostate cancer and may cause its progression [108].

In the prostate cancer, serum level of miR-141 is elevated [109]. So it acts as the biomarker of prostate cancer. In the progression or repression of prostate cancer, miR-141 function is understood poorly [110]. One other study is done by Waltering et al. in which miR-141 is castrated and results in upregulation and activation (**Figure 8**). This causes the LNCaP cell growth to increase. This miRNA is also involved in the regulation of signaling of the androgen. This androgen has a crucial role in the growth of prostate cancer (castration-resistant and androgendependent). So it may be involved in the progression of prostate cancer [111, 112].

In a study involving prostate cancer, miR-888 was found to be upregulated. Its target is the tumor suppressors SMAD4 and RBL1. Binding of this miRNA to the 30 UTR causes their downregulation. RBL1 is the member of the RB (retinoblastoma) family and blocks the progression of cells at the G1-S phase following its binding and inhibition of the transcription factor E2F. SMAD4 protein binds to SMAD receptors and transduces the signal initiated by TGF-β/BMP ligands in order to regulate differentiation and cell growth [113].

In another study, there is the downregulation of miR-23a, b (**Table 10**). There is upregulation of the-Myc gene which causes the repression of these miRNAs at the transcriptional level. Mitochondrial glutaminase protein is expressed in the prostate

**Figure 8.** *miRNA and prostate cancer.*


#### **Table 10.**

*MicroRNAs activating the prostate cancer.*

cancer cells. Consequently, glutamine catabolism is increased, providing a growth advantage to the cancer cells [114].

In another study, miR-34a is suppressed in prostate cancer. The target of miR-34a is deacetylase sirtuin (SIRT1) and cyclin-dependent kinase 6 (CDK6). CDK6 regulates cyclin D, which, in turn, regulates cell cycle progression and G1-S phase transition, while p53 protein-dependent apoptosis is regulated by SIRT1 via deacetylation and stabilization of p53. The target of the p53 gene is miR-34a. It is suggested that there is a positive feedback loop in which SIRT1 mediates the activation of miR-34a via stabilization of p53 and induces the apoptosis and blocks the cell cycle transition. This activation of p53 causes the upregulation of miR-34a which in turn suppresses the SIRT1 (**Table 11**) [114].

#### **5.6 Lung cancer**

The leading cause of death around the world is lung cancer by tobacco smoke. This environmental lifestyle-related factor may cause undesirable epigenetic and genetic modifications [115]. The key role in lung cancer is the alteration and mutation in tumor suppressor genes (p53 and *RB/p16pathway)* and less frequent is the genetic alteration of *FHIT*, *K-ras*, *MYO18B*, and *PTEN* [116].

Five miRNAs were differentially expressed in lung cancer tissues, and these include miR-21, miR-155, miR-145, miR-17-3p, and hsa-let-7a-2. Specifically, hsamiR-155 levels were increased, while that of hsa-let-7a-2 was downregulated [117].

This cluster in lung cancer is transactivated via MYC and members of the E2F family. The direct target of this cluster is HIF-1α. Upregulation of MYC causes the downregulation of HIF-1α and affects proliferation of cell in normoxia without affecting the hypoxic condition. Overexpression of this cluster causes knockdown of retinoblastoma gene and results in the formation of reactive oxygen species. Another direct target of this cluster is RAS-related protein 14 (RAB-14), and it is downregulated by this cluster and results in the initiation and development of

In another study, miR-21 is upregulated in the lung cancer. Its direct target is

In another study, miR-34 is downregulated in the lung cancer. This miRNA is directly regulated by p53 and regulates the apoptosis and arrest of the cell cycle in

The miR-34/miR-499 is downregulated in lung cancer and its direct target is E2F

The miR-15/miR-16 is downregulated in lung cancer. There is upregulation of

and p53 (**Table 13**). Both miRNAs suppress the E2F and upregulate the p53 via

cyclin D1 with the downregulation of miR-15/miR-16. The overexpression of

miR-15/miR-16 causes the arrest of the cell cycle at G1 phase [122]

tumor suppressor gene PTEN that is repressed by overexpression of miR-21 (**Table 12**), which results in cell growth enhancement and non-small cell lung carcinoma invasion [123]. miR-21 is upregulated by RAS via PI3K and RAF/MAPK

cancer [122].

**Figure 9.**

*miRNA and lung cancer.*

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

pathways [122].

SIRT1 so cell growth is increased [124].

cancer [81].

**15**

There is a functional interaction of let-7 with the Ras as a target gene is overexpressed associated with protein kinase and resulting intracellular pathway of signaling [118]. The molecular mechanism is unclear involving miRNA in lung cancer. Alteration in the somatic genes resulted in the defective miRNA expression in lung cancer. This reduced expression of miRNA (has-let-7a-2) in the lung cancer is due to epigenetic modification and results in the silencing of tumor suppressor gene and many others (**Figure 9**) [119, 120]. The expression of hsa-miR-21 is upregulated in cancer cell and causes the inhibition of product of gene which initiates apoptosis and causes lung cancer [121]. In a report miR-1792 cluster is overexpressed in the lung cancer. This cluster consists of six miRNAs.


**Table 11.** *MicroRNAs suppressing the prostate cancer [114].* *MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

**Figure 9.** *miRNA and lung cancer.*

cancer cells. Consequently, glutamine catabolism is increased, providing a growth

**Sr. no. MicroRNAs Potential targets Function Ref.**

141 treatment

Decreased growth in response to anti-miR-

G1-S phase transition [113]

[112]

1 miR-141 LNCaP cells Promote cell growth

In another study, miR-34a is suppressed in prostate cancer. The target of miR-34a is deacetylase sirtuin (SIRT1) and cyclin-dependent kinase 6 (CDK6). CDK6 regulates cyclin D, which, in turn, regulates cell cycle progression and G1-S phase transition, while p53 protein-dependent apoptosis is regulated by SIRT1 via deacetylation and stabilization of p53. The target of the p53 gene is miR-34a. It is suggested that there is a positive feedback loop in which SIRT1 mediates the activation of miR-34a via stabilization of p53 and induces the apoptosis and blocks the cell cycle transition. This activation of p53 causes the upregulation of miR-34a

The leading cause of death around the world is lung cancer by tobacco smoke. This environmental lifestyle-related factor may cause undesirable epigenetic and genetic modifications [115]. The key role in lung cancer is the alteration and mutation in tumor suppressor genes (p53 and *RB/p16pathway)* and less frequent is the

Five miRNAs were differentially expressed in lung cancer tissues, and these include miR-21, miR-155, miR-145, miR-17-3p, and hsa-let-7a-2. Specifically, hsamiR-155 levels were increased, while that of hsa-let-7a-2 was downregulated [117]. There is a functional interaction of let-7 with the Ras as a target gene is overexpressed associated with protein kinase and resulting intracellular pathway of signaling [118]. The molecular mechanism is unclear involving miRNA in lung cancer. Alteration in the somatic genes resulted in the defective miRNA expression in lung cancer. This reduced expression of miRNA (has-let-7a-2) in the lung cancer is due to epigenetic modification and results in the silencing of tumor suppressor gene and many others (**Figure 9**) [119, 120]. The expression of hsa-miR-21 is upregulated in cancer cell and causes the inhibition of product of gene which initiates apoptosis and causes lung cancer [121]. In a report miR-1792 cluster is

advantage to the cancer cells [114].

*MicroRNAs activating the prostate cancer.*

*Current Cancer Treatment*

2 miR-888 Downregulates SMAD4 and RBL1

**5.6 Lung cancer**

**Table 11.**

**14**

**Table 10.**

which in turn suppresses the SIRT1 (**Table 11**) [114].

genetic alteration of *FHIT*, *K-ras*, *MYO18B*, and *PTEN* [116].

overexpressed in the lung cancer. This cluster consists of six miRNAs.

1 miR-23a,b Glutaminase protein (indirect) Glutamine catabolism

2 miR-34a SIRT1 and CDK6 Progression of cell cycle, G1-S phase

transition, and antiapoptosis

**Sr. no. MicroRNAs Potential targets Function**

*MicroRNAs suppressing the prostate cancer [114].*

This cluster in lung cancer is transactivated via MYC and members of the E2F family. The direct target of this cluster is HIF-1α. Upregulation of MYC causes the downregulation of HIF-1α and affects proliferation of cell in normoxia without affecting the hypoxic condition. Overexpression of this cluster causes knockdown of retinoblastoma gene and results in the formation of reactive oxygen species. Another direct target of this cluster is RAS-related protein 14 (RAB-14), and it is downregulated by this cluster and results in the initiation and development of cancer [122].

In another study, miR-21 is upregulated in the lung cancer. Its direct target is tumor suppressor gene PTEN that is repressed by overexpression of miR-21 (**Table 12**), which results in cell growth enhancement and non-small cell lung carcinoma invasion [123]. miR-21 is upregulated by RAS via PI3K and RAF/MAPK pathways [122].

In another study, miR-34 is downregulated in the lung cancer. This miRNA is directly regulated by p53 and regulates the apoptosis and arrest of the cell cycle in cancer [81].

The miR-34/miR-499 is downregulated in lung cancer and its direct target is E2F and p53 (**Table 13**). Both miRNAs suppress the E2F and upregulate the p53 via SIRT1 so cell growth is increased [124].

The miR-15/miR-16 is downregulated in lung cancer. There is upregulation of cyclin D1 with the downregulation of miR-15/miR-16. The overexpression of miR-15/miR-16 causes the arrest of the cell cycle at G1 phase [122]


#### **Table 12.**

*MicroRNAs activating the lung cancer.*


Lim found that miR-196b is upregulated in the gastric cancer (**Table 14**). This miRNA is present in chromosome 9 at HOXA cluster. There is a positive association of expression of miR-196b with the expression of HOXA10. Unmethylation of CpG islands results in the expression of miR-196b. The HOXA10 expression results in hematopoietic stem cell proliferation and progenitor cell proliferation leading to the development of cancer via expression of genes that codes for integrin-β3, TGFβ2,

We studied miR-375 is downregulated in gastric cancer (**Table 15**). Its expression in cancer cell causes the decrease in cell viability by downregulation of PDK1 and JAK2 revealing that miR-375 is a tumor suppressor in gastric cancer [136, 137]. In another study, miR-135a is a tumor suppressor in gastric cancer. Upregulation of miR-135a causes the suppression of gastric cancer via suppression of proliferation of cell via E2F, metastasis, and EMT. In gastric cancer, lymph node metastasis is associated with proliferation, metastasis, and EMT which is suppressed by

**Sr. no. MicroRNAs Potential targets Function Ref.** 1 miR-106b-25 E2F1 Antiapoptosis and cell proliferation [132]

cell proliferation

metastasis, and EMT

[135]

[138]

2 miR-196b HOXA10 Progenitor and hematopoietic stem

**Sr. no. MicroRNAs Potential targets Function Ref.** 1 miR-375 PDK1 and JAK2 Decrease the cell viability [136, 137]

2 miR-135a E2F Suppress cell proliferation,

and dual-specificity protein phosphatase 4 [135].

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

overexpression of miR135a [138].

*MicroRNAs activating the gastric cancer.*

*MicroRNAs suppressing the gastric cancer.*

**Figure 11.**

**Table 14.**

**Table 15.**

**17**

*miRNA and gastric cancer.*

#### **Table 13.**

*MicroRNAs suppressing the lung cancer.*

#### **5.7 Gastric cancer**

The second malignancy that is widely prevailed is the gastric cancer which results in 12% deaths around the world [125]. Gastric cancer is the result of a series of steps. When transforming growth factor (TGF-beta) resistance is developed and E2F1 is upregulated, then gastric cancer is developed [126, 127].

In gastric cancer, there is upregulation of cluster of miR-106b-25 present on Mcm gene [128]. The transition of the G1/S phase of the cell cycle is targeted by Mcm gene. It ensures that DNA is replicated only one time when replication fork is assembled on the DNA during each cycle [129]. When cells exit from the mitosis, then expression of cluster of miR-106b-25 is activated by E2F1 (**Figure 10**) and gains the reentry in the G1 phase of the cell cycle. The cell cycle inhibitor is p21 [130].

The cytokine TGF-beta causes the cell cycle arrests by activating p21 and causes the apoptosis [131]. As this cytokine is activated it causes the downregulation of miR-106b-25 cluster, reduces the expression of E2F1, causes the cell cycle arrest at G1/S phase of cell cycle, and causes the induction of apoptosis. The key target of miR-93 and miR-106b is E2F1 [132]. The key target of miR-25, the biomarker of gastric cancer, is TGF-beta cytokine [133]. The target of cytokine in mediating the apoptosis is Bim protein that in turn causes the activation of proapoptotic Bax and Bad molecules acting as an antagonist of Bcl2 and BclXL antiapoptotic factors (**Figure 11**) [134].

**Figure 10.** *miR-106b-25 cluster.*

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

**Figure 11.** *miRNA and gastric cancer.*

**5.7 Gastric cancer**

*MicroRNAs suppressing the lung cancer.*

*MicroRNAs activating the lung cancer.*

*Current Cancer Treatment*

**Table 13.**

**Table 12.**

p21 [130].

(**Figure 11**) [134].

**Figure 10.** *miR-106b-25 cluster.*

**16**

The second malignancy that is widely prevailed is the gastric cancer which results in 12% deaths around the world [125]. Gastric cancer is the result of a series of steps. When transforming growth factor (TGF-beta) resistance is developed and

**Sr. no. MicroRNAs Potential targets Function Ref.**

**Sr. no. MicroRNAs Potential targets Function Ref.**

1 let-7 Ras Protein kinase-associated

2 miR-1792 HIF-1α and RAB14 ROS and initiation and

3 miR-21 PTEN Cell growth enhancement

2 miR-34/miR-499 E2F and p53 Cell growth and proliferation [124]

arrest of cell cycle

signaling pathway

and invasion

development of cancer

the G1 phase

[81]

[118]

[122]

[122]

[122]

1 miR-34 p53 Regulate the apoptosis and

3 miR-15/miR-16 Cyclin D1 The arrest of the cell cycle at

In gastric cancer, there is upregulation of cluster of miR-106b-25 present on Mcm gene [128]. The transition of the G1/S phase of the cell cycle is targeted by Mcm gene. It ensures that DNA is replicated only one time when replication fork is assembled on the DNA during each cycle [129]. When cells exit from the mitosis, then expression of cluster of miR-106b-25 is activated by E2F1 (**Figure 10**) and gains the reentry in the G1 phase of the cell cycle. The cell cycle inhibitor is

The cytokine TGF-beta causes the cell cycle arrests by activating p21 and causes the apoptosis [131]. As this cytokine is activated it causes the downregulation of miR-106b-25 cluster, reduces the expression of E2F1, causes the cell cycle arrest at G1/S phase of cell cycle, and causes the induction of apoptosis. The key target of miR-93 and miR-106b is E2F1 [132]. The key target of miR-25, the biomarker of gastric cancer, is TGF-beta cytokine [133]. The target of cytokine in mediating the apoptosis is Bim protein that in turn causes the activation of proapoptotic Bax and Bad molecules acting as an antagonist of Bcl2 and BclXL antiapoptotic factors

E2F1 is upregulated, then gastric cancer is developed [126, 127].

Lim found that miR-196b is upregulated in the gastric cancer (**Table 14**). This miRNA is present in chromosome 9 at HOXA cluster. There is a positive association of expression of miR-196b with the expression of HOXA10. Unmethylation of CpG islands results in the expression of miR-196b. The HOXA10 expression results in hematopoietic stem cell proliferation and progenitor cell proliferation leading to the development of cancer via expression of genes that codes for integrin-β3, TGFβ2, and dual-specificity protein phosphatase 4 [135].

We studied miR-375 is downregulated in gastric cancer (**Table 15**). Its expression in cancer cell causes the decrease in cell viability by downregulation of PDK1 and JAK2 revealing that miR-375 is a tumor suppressor in gastric cancer [136, 137].

In another study, miR-135a is a tumor suppressor in gastric cancer. Upregulation of miR-135a causes the suppression of gastric cancer via suppression of proliferation of cell via E2F, metastasis, and EMT. In gastric cancer, lymph node metastasis is associated with proliferation, metastasis, and EMT which is suppressed by overexpression of miR135a [138].


#### **Table 14.**

*MicroRNAs activating the gastric cancer.*


**Table 15.** *MicroRNAs suppressing the gastric cancer.*

#### **5.8 Bladder cancer**

In males, bladder cancer is an important malignancy present in two forms that are muscle invasive and non-muscle invasive (benign) [139]. There are two microRNAs associated with bladder cancer. They are miR-21 and miR-129 [140].

genes in bladder cancer. Over expression of miR-34a causes the inhibition of invasion, metastasis, migration, tube formation, and angiogenesis by targeting the

Glioblastoma is the tumor of astrocytes, star-shaped cells that form the supportive tissues (glue-like) of the brain. This is readily metastasizing tumor because it is surrounded by large blood vessels. Glioblastoma is a complex and heterogeneous tumor that comprises on neoplastic cells, endothelial cells, stemlike cells, neural precursor cells, microglia, reactive extracellular components, and peripheral

The biomarker in glioblastoma is miR-21 that is upregulated in this cancer (**Figure 13**). It mediates its effect in two ways: acting at the translational level and

apoptosis) [148] and causes the inhibition of transcription of apoptotic genes by decreasing the stability. It also resists the caspases 3 and 7 that are important

targets the p57 and p27 (inhibitors of cell-dependent kinase) to prevent the quiescence at G1 phase and cause their entry to S phase of the cell cycle. The miR-221/miR-222 also targets the PUMA, a proapoptotic protein, to prevent the

Another biomarker miR-128 is found to be downregulated in glioblastoma. The expression of miR-128 causes the regulation of proliferation of glioblastoma multiform (GBM) cells via targeting the PDGFR-α and EGFR, the oncogenic kinases

**Sr. no. MicroRNAs Potential targets Function Ref.** 1 miR-21 Caspases 3 and 7 Antiapoptotic [149]

2 miR-221/miR-222 Cyclin-dependent kinase

1B/p27

Upregulation of miR-221 and miR-222 was in glioma cells. These two miRNAs present as a cluster on Xp11.3 and have the same target. Functional studies revealed that there is an association of these two miRNAs with the progression of the cell cycle. Their direct target is cyclin-dependent kinase 1B/p27. The overexpression of these miRNAs cause the activation of quiescent glioblastoma cells and the progression of these cells from G1 phase to S phase of the cell cycle. miR-221/miR-222 also

UTR region of the target gene (for

Prevent the apoptosis [150]

CD44 [146].

**5.9 Glioblastoma**

immune cells [147].

apoptosis (**Table 18**) [150].

**Figure 13.**

**Table 18.**

**19**

*miRNA and glioblastoma.*

*MicroRNAs activating the glioblastoma.*

acting at the transcription level. It binds the 3<sup>0</sup>

*MicroRNA: A Signature for Cancer Diagnostics DOI: http://dx.doi.org/10.5772/intechopen.90063*

apoptotic agents so apoptosis does not occur [149].

In the bladder cancer, miR-129 and miR-21 both are upregulated. The direct target of miR-21 is the tumor suppressor genes that are TPM1 and PTEN (**Figure 12**) [141, 142]. The known targets of miR-129 are the genes involved in the regulation of transcription and processing of miRNA that are TAMTA1 and EIF2CA [143]. The mir-129's pathway of death effectors leads to the tumor as its target is also SOX4 [144].

According to one study, miR-19a is frequently upregulated in the bladder cancer. The expression of miR-19a is related to PTEN expression (**Table 16**). PTEN is a tumor suppressor gene. When miR-19a is overexpressed, it causes the downregulation of PTEN and increases the cell level of phosphatidylinositol-3,4,5 trisphosphate in AKT/PKB pathway. When growth factors are released, then the AKT pathway is initiated and cell growth is increased [145].

Zhang studied that miR-125b is downregulated in bladder cancer. The expression of miR-135b causes the inhibition of formation of colony and development of cancer via suppression of E2F3 which is overexpressed in bladder cancer [74].

In another study angiogenesis in the bladder cancer is suppressed by miR-34a (**Table 17**). The target of miR-34a is CD44 and causes the suppression of CD44 when upregulated which results in the regulation of transcription of the various

**Figure 12.** *miRNA and bladder cancer.*


#### **Table 16.**

*MicroRNAs activating the bladder cancer.*


**Table 17.** *MicroRNAs suppressing the bladder cancer.*

genes in bladder cancer. Over expression of miR-34a causes the inhibition of invasion, metastasis, migration, tube formation, and angiogenesis by targeting the CD44 [146].
