**Figure 2.**

**2. Synthesis/biogenesis of miRNA**

*Current Cancer Treatment*

each 3<sup>0</sup>

Synthesis of miRNA takes place in the nucleus as well as in the cytoplasm. Genes encoding miRNAs are present in the form of a cluster and contain introns (**Figure 1**). These genes are transcribed by polymerase II with the generation of the primary precursor pri-miRNA. This precursor miRNA consists of a 3<sup>0</sup> poly-A tail and a 5<sup>0</sup> end cap [19, 20] with a stem-loop structure. RNase 3 Drosha cleaves this structure with the help of its Pasha cofactor DGCR8. This resultant cleaved, precursor structure is known as pre-miRNA and consists of �70–90 nucleotides [21].

In the cytoplasm, the whole pri-miRNA is recruited by a RNA-induced silencing complex (RISC) and is converted into mature miRNA. These are mediated by an RISC leaching complex (RLS), which is basically a multiprotein complex and consists of a double-stranded RNA domain protein (DICER), tar RNA-binding protein (TARB), and the Ago 2 protein. The RNAse 3 DICER along with its cofactor yields duplex miRNA (19–25 nucleotide duplex miRNA with 2 nucleotide overhangs at

end). During the process of cleavage, two strands are formed, namely, a functional and a passenger strand. The functional strand along with the Ago protein

(RISC) is involved in gene silencing function, while the passenger strand is degraded due to its instability. This miRISC incorporates one strand of miRNA (functional strand and guide strand) so that it takes the guidance from this complex to target mRNA (complementary) for its degradation or inhibition at the translational level [22]. miRNA is processed in the cytosol and transported to the blood. It is resistant to degradation because it is carried by complexes of lipoprotein

The mechanism of action of microRNA is such that it binds to its partial complementary sequence in the target mRNA (that codes for protein). Hence, the

In another scenario, the microRNA may bind to the complementary sequence of target mRNA that codes for protein and initiates RNA-mediated gene silencing,

expression is repressed (**Figure 2**) and no product is synthesized [7].

with the resultant cleavage of the target RNA (**Figure 3**) [26].

inclusions [23] or in the form of exosomes [24, 25].

**3. Mechanism of action**

*Biogenesis of microRNA.*

**Figure 1.**

**4**

This �70 nt precursor is exported to the cytoplasm by Exportin-5.

*Mechanism of action of miRNA.*

### **4. Diagnosis of cancer**

There are reported differences in the expression pattern of miRNA in normal and cancer cells [27]. Some miRNAs are overexpressed, while the others are downregulated in different kinds of cancers [28]. Due to its small size and resistance to RNase-mediated degradation, they have the potential as powerful biomarkers for cancer diagnosis [29]. miRNA expression is involved with the rearrangement of chromosomes, methylation of the promoter region, and transcriptional regulation. miRNA-mediated aberrations in one or more of these processes can culminate in alterations in protein and mRNA expression [30].

#### **5. Types of miRNA and cancer according to organs**

Different miRNAs are involved in different types of cancers:

#### **5.1 Breast cancer**

Breast cancer is the most prevalent form of cancer in women. Among 12.7 million cancer cases globally, breast cancer is most frequently diagnosed, that is, 23 and 14% deaths due to breast cancer have been reported [1, 31]. The alarmingly increasing mortality data coupled with increases in relapses warrants an improved molecular understanding of the etiology and mechanistic details that contribute to the chemoresistance. There are four subtypes (intrinsic) of breast cancer. These are ErbB2<sup>+</sup> (epidermal growth factor receptor 2-positive (also called HER2)), luminal A (hormone receptor positive for estrogen and progesterone, HER2), luminal B (hormone receptor positive for estrogen and progesterone and positive or negative for HER2), and basal like (hormone receptors negative for estrogen, progesterone, and HER2) showing its heterogeneity. Many of the microRNAs play a role in the inhibition of breast cancer. The upregulation of miR-21 (**Table 1**) results in the increased expression of BCL-2 protein and chemoresistance in breast cancer [38]. MiR-125b shows the resistance to chemotherapeutic agents 5-fluorouracil, and it has higher expression in the patients that are nonresponsive to this agent (**Table 2**). Many promote the prognosis of breast cancer by targeting the tumor suppressor at the gene level and activating the transcriptional factors that are oncogenic in nature [32, 38].

The Rab protein is a member of the Ras superfamily (**Figure 4**). This protein is a G-protein-coupled receptor and is involved in many cellular processes including fusion, budding, synthesis of vesicles, and motility [55]. A member of the Rab class is Rab11a, and this protein has many functions including cellular migration and phagocytosis [56]. In breast cancer there is overexpression of Rab11a protein [57] and is regulated by miRNA 320a. This miRNA can downregulate Rab11a protein, thereby mediating the inhibition of breast cancer progression.

MiR-320a has an important role in tumor suppression [58] and can be a biomarker for breast cancer. This miR-320a results in a 15% increase of cells in G0/G1,


*Meta-analysis or Cochrane reviews documenting the involvement of a specific miRNA or a battery of miRNAs contributing to relapse or recurrence can be displayed as a separate table for each of the cancers.*

and the population of cells in the S phase is decreased. Apart from the G0/G1 cell cycle arrest, miR-320a also increases the activity of caspase resulting in the induction of apoptosis [59]. The potential target of miR-20 is Rab11a; it has two binding

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

Inhibition of cellular differentiation and proliferation

Inhibition of cellular proliferation

Inhibition of invasion and

Promotes the antitumoral activity of natural killer cells and reduction in metastasis

migration, and metastasis

Reduction in survival and metastasis via interleukin 6

Reduction in angiogenesis

metastasis and invasion for

Reduction in the metastasis and progression of cancer

and progression of cancer

Reduction in tumor growth, EMT through E-cadherin,

migration

proliferation

and metastasis

and metastasis

and metastasis

inhibition

[41]

[42]

[43, 44]

[45, 46]

[47]

[48]

[49]

[50]

[51]

[52]

[38]

[53]

[54]

receptors (positive correlation with ERBB2/HER2 expression)

Glutamyl aminopeptidase or aminopeptidase A, casein kinase 2 alpha, cyclin J, multiple EGF-like

Receptor tyrosine-protein kinase erbB-2 (human epidermal growth factor receptor 2) (induction of miR cause the downregulation of ERBB2/

2 miR-205 High-mobility group box 3 gene Suppression of invasion and

4 miR-206 Cyclin D2, connexin 43 Reduction in invasion,

1/2, snail family zinc finger ½

transducer, and activator of

protein 2, c-Mer tyrosine kinase, phosphatidylinositol transfer protein,

8 miR-335 SRY-related HMG-box 4, tenascin C Suppression in migration

9 miR-31 Ras homolog gene family Targets various steps of

WAS protein family, member 3, Ras

homolog gene family

*MicroRNAs downregulating the breast cancer.*

1 miR-125b Erythropoietin, erythropoietin

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

domains 9

ERBB3)

3 miR-17-92 Mitogen-activated protein kinase kinase kinase 2

5 miR-200 Zinc finger E-box binding homeobox

transcription 3

7 miR-126 Insulin-like growth factor-binding

cytoplasmic 1

6 miR-146b Nuclear factor kappa B, signal

repression. This protein is also necessary for the activation of Akt via phosphatidylinositol-4-kinase (PI4K3) in breast cancer—a pro-survival signal [60]. Further, overexpression of Rab11a protein results in the reversal of cell cycle arrest and

coding for the Rab coupling protein (RCP) (a Rab11-FIP1C (Rab coupling protein))

apoptosis mediated by miR-320a by targeting the MTDH at 3<sup>0</sup>

UTR region for miR-320a and can mediate its posttranscriptional

WAS protein family, member 3 Reduction in the metastasis

UTR [61]. The gene

sites at the 3<sup>0</sup>

**7**

**Table 2.**

#### **Table 1.**

*MicroRNAs upregulating the breast cancer.*

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

(hormone receptor positive for estrogen and progesterone, HER2), luminal B (hormone receptor positive for estrogen and progesterone and positive or negative for HER2), and basal like (hormone receptors negative for estrogen, progesterone, and HER2) showing its heterogeneity. Many of the microRNAs play a role in the inhibition of breast cancer. The upregulation of miR-21 (**Table 1**) results in the increased expression of BCL-2 protein and chemoresistance in breast cancer [38]. MiR-125b shows the resistance to chemotherapeutic agents 5-fluorouracil, and it has higher expression in the patients that are nonresponsive to this agent (**Table 2**). Many promote the prognosis of breast cancer by targeting the tumor suppressor at the gene level and activating the transcriptional factors that are oncogenic in

The Rab protein is a member of the Ras superfamily (**Figure 4**). This protein is a G-protein-coupled receptor and is involved in many cellular processes including fusion, budding, synthesis of vesicles, and motility [55]. A member of the Rab class is Rab11a, and this protein has many functions including cellular migration and phagocytosis [56]. In breast cancer there is overexpression of Rab11a protein [57] and is regulated by miRNA 320a. This miRNA can downregulate Rab11a protein,

MiR-320a has an important role in tumor suppression [58] and can be a biomarker for breast cancer. This miR-320a results in a 15% increase of cells in G0/G1,

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

migration, and metastasis by targeting the RhoC

Promotes cellular invasion, metastasis, epithelial-tomesenchymal transition and

Promotes cellular invasion [33]

Promotes cellular invasion [34]

Promotes cell proliferation [36]

Promotes cell proliferation and

Promotes cellular invasion and

Promotes cellular invasion and

invasion, and metastasis

migration

growth

cell survival

migration

metastasis

Forkhead box protein O3 Promotes cell proliferation and

[32]

[35]

[37, 38]

[39]

[40]

[39]

1 miR-10b Homeobox D10 Promotes cellular invasion,

protein 4, hypoxiainducible factor-1α

Phosphatase and tensin homolog, programmed cell

Metalloproteinase inhibitor

Suppressor of cytokine

5 miR-520c Promotes cellular migration,

*contributing to relapse or recurrence can be displayed as a separate table for each of the cancers.*

*Meta-analysis or Cochrane reviews documenting the involvement of a specific miRNA or a battery of miRNAs*

Tumor protein p53 inducible nuclear protein

death protein 4, tropomyosin 1

3

signaling 1

correlated)

thereby mediating the inhibition of breast cancer progression.

2 miR-21 Programmed cell death

nature [32, 38].

*Current Cancer Treatment*

3 miR-155

**Table 1.**

**6**

(chemosensitive determinant by targeting the FOXO3)

*MicroRNAs upregulating the breast cancer.*

4 miR-373 CD44 (inversely


**Table 2.**

*MicroRNAs downregulating the breast cancer.*

and the population of cells in the S phase is decreased. Apart from the G0/G1 cell cycle arrest, miR-320a also increases the activity of caspase resulting in the induction of apoptosis [59]. The potential target of miR-20 is Rab11a; it has two binding sites at the 3<sup>0</sup> UTR region for miR-320a and can mediate its posttranscriptional repression. This protein is also necessary for the activation of Akt via phosphatidylinositol-4-kinase (PI4K3) in breast cancer—a pro-survival signal [60]. Further, overexpression of Rab11a protein results in the reversal of cell cycle arrest and apoptosis mediated by miR-320a by targeting the MTDH at 3<sup>0</sup> UTR [61]. The gene coding for the Rab coupling protein (RCP) (a Rab11-FIP1C (Rab coupling protein))

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

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

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

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

> Reduction in the proliferation, induction of cell cycle arrest at the G1 stage, and

> > Enhances the cell proliferation and

promotion of apoptosis

having colorectal adenoma [76–78].

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

miR-195 and miR-497 is reduced [87].

proteins targeting p53 and pRb, respectively [91].

1 miR-185 Ras homolog gene family, member

42 homolog

1 miR-130a Mothers against decapentaplegic

*MicroRNAs suppressing the colorectal cancer [80].*

*MicroRNAs promoting the colorectal cancer [80].*

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

A, and cell division control protein

2 miR-192 cyclin-dependent kinase inhibitor 1 Regulating the p53

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

migration 2 miR-301a

4 miR-200 Zinc finger E-box-binding homeobox ½ Promotes metastasis

homolog 4 (SMAD4)

4 miR-34a Tumor suppressor p53 Modulate the EMT transition

**5.3 Cervical cancer**

3 miR-215

3 miR-454

**Table 3.**

**Table 4.**

**9**

microRNA is miR-34a [82].

#### **Figure 4.** *MicroRNA and breast 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 phenotype of breast cancer [64, 65].
