Open access peer-reviewed chapter

MicroRNA: A Signature for Cancer Diagnostics

Written By

Ayesha Siddiqua, Sumaira Kousar, Amer Jamil, Riaz Tabassum, Tariq Mehmood and Nusrat Shafiq

Submitted: August 26th, 2018 Reviewed: October 9th, 2019 Published: February 13th, 2020

DOI: 10.5772/intechopen.90063

Chapter metrics overview

957 Chapter Downloads

View Full Metrics


Various tools and techniques are being used for the diagnosis of cancer, but not a sole technique provides powerful result at the very early stages of cancer. This provides the need for type of tools which could detect cancer at early stages so that survival rate could be augmented. There are various diagnostic ways to identify cancer, but in each case, there are always circumstances to compromise on the sensitivity. In this framework, a new and more advanced approach of diagnosis for cancer is microRNA (miRNA). miRNAs are conserved regions among humans and animals, and their synthesis takes place in the nucleus and cytoplasm. There are several types of microRNAs that could be upregulated and downregulated in various cancers. A cancer cell could be identified by measurement of the expression pattern of miRNA. By examining the expression level for different types of cancers, miRNA can be used as biomarker for early detection of cancer in human beings.


  • microRNA
  • cancer biomarker
  • diagnostic
  • colorectal
  • upregulation
  • downregulation
  • breast cancer
  • cervical
  • liver
  • prostate

1. Introduction

MicroRNAs (miRNAs) are a small, non-coding, single-stranded RNA consisting of around 22 nucleotides [1]. More than 3% of the human genome (gene portion) encodes for microRNA, and their number is around 1000 [2, 3, 4]. This small RNA can regulate gene expression posttranscriptionally [5, 6, 7]. This small RNA can regulate gene expression posttranscriptionally by binding to its cognate RNA target at the 30 untranslated region (UTR) [8, 9, 10, 11]. A small microRNA was discovered for the first time in C. elegansand is encoded by the Lin-4 gene [12] providing evidence for its evolutionary conservation. This conserved microRNA was found to be involved in many important biological processes including cell proliferation, growth, apoptosis, etc. [13, 14], and many cell-based factors have been known to regulate its expression [15]. The genes transcribing the miRNA are considered to belong to the set of tumor suppressor genes, and the serum level of miRNA can be detected [16, 17]. There are certain miRNAs that can behave as either oncomiRs (whose expression can cause the cancer) or tumor suppressor depending on the context “Several miRNAs cannot be clearly and unequivocally categorized as tumor suppressors or oncomiRs because data in our hands are quite intricate and conflicting since they could act as tumor suppressors in one scenario or as oncomiRs in the other” [18].


2. Synthesis/biogenesis of miRNA

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′ poly-A tail and a 5′ 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]. This ∼70 nt precursor is exported to the cytoplasm by Exportin-5.

Figure 1.

Biogenesis of microRNA.

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 each 3′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 inclusions [23] or in the form of exosomes [24, 25].


3. Mechanism of action

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

Figure 2.

Mechanism of action of miRNA.

In another scenario, the microRNA may bind to the complementary sequence of target mRNA that codes for protein and initiates RNA-mediated gene silencing, with the resultant cleavage of the target RNA (Figure 3) [26].

Figure 3.

Mechanism 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+ (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].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-10bHomeobox D10Promotes cellular invasion, migration, and metastasis by targeting the RhoC[32]
2miR-21Programmed cell death protein 4, hypoxia-inducible factor-1αPromotes cellular invasion, metastasis, epithelial-to-mesenchymal transition and migration
Phosphatase and tensin homolog, programmed cell death protein 4, tropomyosin 1Promotes cellular invasion[33]
Metalloproteinase inhibitor 3Promotes cellular invasion[34]
3miR-155 (chemosensitive determinant by targeting the FOXO3)Suppressor of cytokine signaling 1Promotes cell proliferation and growth[35]
Tumor protein p53 inducible nuclear proteinPromotes cell proliferation[36]
Forkhead box protein O3Promotes cell proliferation and cell survival[37, 38]
4miR-373CD44 (inversely correlated)Promotes cellular invasion and migration[39]
Promotes cellular invasion and metastasis[40]
5miR-520cPromotes cellular migration, invasion, and metastasis[39]

Table 1.

MicroRNAs upregulating the breast cancer.

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.

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-125bErythropoietin, erythropoietin receptors (positive correlation with ERBB2/HER2 expression)Inhibition of cellular differentiation and proliferation[41]
Glutamyl aminopeptidase or aminopeptidase A, casein kinase 2-alpha, cyclin J, multiple EGF-like domains 9Inhibition of cellular proliferation[42]
Receptor tyrosine-protein kinase erbB-2 (human epidermal growth factor receptor 2) (induction of miR cause the downregulation of ERBB2/ERBB3)Inhibition of invasion and migration[43, 44]
2miR-205High-mobility group box 3 geneSuppression of invasion and proliferation[45, 46]
3miR-17-92Mitogen-activated protein kinase kinase kinase 2Promotes the antitumoral activity of natural killer cells and reduction in metastasis[47]
4miR-206Cyclin D2, connexin 43Reduction in invasion, migration, and metastasis[48]
5miR-200Zinc finger E-box binding homeobox 1/2, snail family zinc finger ½Reduction in tumor growth, EMT through E-cadherin, and metastasis[49]
6miR-146bNuclear factor kappa B, signal transducer, and activator of transcription 3Reduction in survival and metastasis via interleukin 6[50]
7miR-126Insulin-like growth factor-binding protein 2, c-Mer tyrosine kinase, phosphatidylinositol transfer protein, cytoplasmic 1Reduction in angiogenesis and metastasis[51]
8miR-335SRY-related HMG-box 4, tenascin CSuppression in migration and metastasis[52]
9miR-31Ras homolog gene familyTargets various steps of metastasis and invasion for inhibition[38]
WAS protein family, member 3, Ras homolog gene familyReduction in the metastasis and progression of cancer[53]
WAS protein family, member 3Reduction in the metastasis and progression of cancer[54]

Table 2.

MicroRNAs downregulating the breast cancer.

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.

Figure 4.

MicroRNA and breast cancer.

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, 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′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′UTR [61]. The gene coding for the Rab coupling protein (RCP) (a Rab11-FIP1C (Rab coupling protein)) 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].

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].

Figure 5.

MicroRNA and colorectal cancer.

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-mediated 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]. 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, 77, 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/STAT3pathway 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].

Sr. no.MicroRNAsPotential targetFunction
1miR-185Ras homolog gene family, member A, and cell division control protein 42 homologReduction in the proliferation, induction of cell cycle arrest at the G1 stage, and promotion of apoptosis
2miR-192cyclin-dependent kinase inhibitor 1Regulating the p53
4miR-34aTumor suppressor p53Modulate the EMT transition

Table 3.

MicroRNAs suppressing the colorectal cancer [80].

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].

Sr. no.MicroRNAsPotential targetFunction
1miR-130aMothers against decapentaplegic homolog 4 (SMAD4)Enhances the cell proliferation and migration
4miR-200Zinc finger E-box-binding homeobox ½Promotes metastasis

Table 4.

MicroRNAs promoting the colorectal cancer [80].

5.3 Cervical cancer

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].

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.

Type of miRNAFunctionRef.
miR-491-5pDownregulated; suppress cervical cancer by telomerase reverse transcriptase and regulate the PI3K/AKT pathway[92]
miR-142-3pInhibit the proliferation of cell Frizzled_7 receptor (FZD7)[93]
miR-142-3pInhibit the growth of cell via downregulation of its FOXM1 target[94]

Table 5.

AmiRNA involved in cervical cancer.

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).

Figure 6.

MicroRNA and cervical cancer.

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].

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-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.

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-196aBinds to the 3′UTR of p27Kip and FOXO1 and inhibits their translationIncreases in cell proliferation and tumorigenesis[97]
2miR-10aHas an inverse relation with the expression of close homolog of L1 (CHL1) transmembrane protein type 1—a cell-adhesion proteinCell growth followed by migration and invasion[91]
3miR-21Negatively regulates p53 and Cdc25, TPM1 and RECK, and PTEN and PDCD4Enhances the expression of genes associated with cell proliferation, metastasis, as well as those involved in the antiapoptosis effect[91]
4miR-886-5pNegatively regulates the Bax geneDysregulation of the gene involved in apoptosis (miR-10a, miR-106b, miR-21, miR-135b, miR-141, miR146, miR-148a, miR-214, and miR-886-5p)[91]
5miR-20aTNKS2 oncogene is upregulated (by binding at 3′UTR of mRNA of TNKS2 results in enhanced translation)Migration, colony formation, and invasion[91]

Table 6.

MicroRNAs activating the cervical cancer.

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].

Sr. no.MicroRNAsPotential targetFunction
1miR-143Target k-Ras, Bcl-2 and Macc1, specifically downregulation of Bcl-2Inhibition of apoptosis and uncontrolled cell proliferation
2miR-129-5pDownregulates HPV18 E5 and E7 expression as well as inhibits the translation of SP-1 transcriptional factorSuppressing the progression of cervical cancer
3miR-34aCyclin E2 and D1, CDK6, E2F3, CDK4, E2F1, E2F5, P18, Bcl-2, and SIRT1Aberrations in cell proliferation and differentiation—cell transformation

Table 7.

MicroRNAs suppressing cervical cancer [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 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].

Figure 7.

MicroRNA and liver cancer.

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′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].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-26aCyclin E2 and D2The arrest of the cell cycle at G1 phase[84]
2miR-31CDK2 protein and HDAC2Suppress the positive regulators of cell cycle and promote those proteins involved in EMT-related processes[102]

Table 8.

MicroRNAs suppressing the liver cancer.

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′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′UTR of these genes [103].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-9Influences the PPARA/CDH1pathwaySuppress the tumor suppressor[103]
2miR-525-3pDownregulates ZNF395Enhances cell growth and prevent apoptosis[104]

Table 9.

MicroRNAs activating the liver cancer.

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 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 androgen-dependent). So it may be involved in the progression of prostate cancer [111, 112].

Figure 8.

miRNA and prostate cancer.

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

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-141LNCaP cellsPromote cell growth
Decreased growth in response to anti-miR-141 treatment
2miR-888Downregulates SMAD4 and RBL1G1-S phase transition[113]

Table 10.

MicroRNAs activating the prostate cancer.

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].

Sr. no.MicroRNAsPotential targetsFunction
1miR-23a,bGlutaminase protein (indirect)Glutamine catabolism
2miR-34aSIRT1 and CDK6Progression of cell cycle, G1-S phase transition, and antiapoptosis

Table 11.

MicroRNAs suppressing the prostate cancer [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, hsa-miR-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-17∼92 cluster is overexpressed in the lung cancer. This cluster consists of six miRNAs.

Figure 9.

miRNA and lung cancer.

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].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1let-7RasProtein kinase-associated signaling pathway[118]
2miR-17∼92HIF-1α and RAB14ROS and initiation and development of cancer[122]
3miR-21PTENCell growth enhancement and invasion[122]

Table 12.

MicroRNAs activating the lung cancer.

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].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-34p53Regulate the apoptosis and arrest of cell cycle[81]
2miR-34/miR-499E2F and p53Cell growth and proliferation[124]
3miR-15/miR-16Cyclin D1The arrest of the cell cycle at the G1 phase[122]

Table 13.

MicroRNAs suppressing the lung cancer.

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]

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].

Figure 10.

miR-106b-25 cluster.

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 11.

miRNA and gastric 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, and dual-specificity protein phosphatase 4 [135].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-106b-25E2F1Antiapoptosis and cell proliferation[132]
2miR-196bHOXA10Progenitor and hematopoietic stem cell proliferation[135]

Table 14.

MicroRNAs activating the gastric cancer.

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].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-375PDK1 and JAK2Decrease the cell viability[136, 137]
2miR-135aE2FSuppress cell proliferation, metastasis, and EMT[138]

Table 15.

MicroRNAs suppressing the gastric cancer.

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].

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].

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].

Figure 12.

miRNA and bladder cancer.

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].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-129TAMTA1 and EIF2CARegulation of transcription[143]
2miR-21TPM1 and PTENGrowth of tumor cell[141]
3miR-19aPTENIncrease in the cell growth[145]

Table 16.

MicroRNAs activating the bladder cancer.

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 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].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-125bE2F3Inhibition of formation of colony and development of cancer[74]
2miR-34aCD44Inhibition of invasion, metastasis, migration, tube formation, and angiogenesis[146]

Table 17.

MicroRNAs suppressing the bladder cancer.

5.9 Glioblastoma

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 immune cells [147].

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 acting at the transcription level. It binds the 3′UTR region of the target gene (for 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 apoptotic agents so apoptosis does not occur [149].

Figure 13.

miRNA and glioblastoma.

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 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 apoptosis (Table 18) [150].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-21Caspases 3 and 7Antiapoptotic[149]
2miR-221/miR-222Cyclin-dependent kinase 1B/p27Prevent the apoptosis[150]

Table 18.

MicroRNAs activating the glioblastoma.

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 (receptor tyrosine kinases) (Table 19). It suppresses the GBM by enhancing the differentiation of neuronal cells. It also targets the signaling molecules in the PI3-kinase/AKT pathway which causes the tumor cell proliferation [147].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-128PDGFR-α and EGFREnhancing the differentiation of neuronal cells[147]
2miR-7EGFRReduction of cell viability[151]

Table 19.

MicroRNAs suppressing the glioblastoma.

In other study miR-7 is downregulated in glioblastoma. Its target is EGFR and causes the inhibition of AKT pathways and EGFR and results in the reduction of cell viability of GBM via direct binding to mRNA of EGFR or via targeting to IRS1 and IRS2 (insulin receptor substrate). The major regulators EGFR and IRS are at upstream site of AKT pathway [151].

5.10 B cell chronic lymphocytic leukemia

This is the cancer of B lymphocytes (antibodies), and it is a prevalent form of leukemia in the adult around western countries [152].

In B cell leukemia, the expression of three microRNAs is seen as cancer biomarker. These are miR-15a, miR-16-1, and miR-19a (Figure 14). Two microRNAs are present at 13q14.3 chromosomal location; these are miR-15a and 16-1 [153]. The expression of these two is decreased in this leukemia, whereas the expression of miR-19a is increased [152]. The region encoding for miR-15a and miR-16-1 was deleted. This leads to the presence of the genes of IgVH that were mutated [154]. The potent target of miR-19a is PTEN, and there is down-expression of this PTEN gene; hence its protein is not properly synthesized because the promoter of the gene is hypermethylated [155].

Figure 14.

miRNA and B cell lymphocytic leukemia.

The miR-16-1 and miR-15a (located on chromosome 13) are downregulated in B cell lymphocytic leukemia (Table 20). These miroRNAs target the p53 gene which is a tumor suppressor gene. When these miRNAs are downregulated, then the expression of p53 is reduced or inhibited, and expression of BCL-2 is increased which prevent the apoptosis and cell survival is increased [156].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-15ap53Prevent the apoptosis and cell survival is increased[153]
2miR-16-1p53Prevent the apoptosis and cell survival is increased[156]

Table 20.

MicroRNAs suppressing the B cell lymphocytic leukemia.

In one study, miR-17/miR-92 cluster is overexpressed in the B cell lymphocytic leukemia (Table 21). The direct target of this cluster is PTEN and Bim. The PTEN is a tumor suppressor gene, and Bim is proapoptotic protein. Overexpression of this cluster causes prevention of apoptosis and progression of tumor [157].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-19aPTENCause the tumor[155]
2miR-17/miR-92PTEN and BimPrevention of apoptosis and progression of tumor[157]
3miR-155SHIP1Inhibition of BCR signaling and surface immunoglobulin[158]

Table 21.

MicroRNAs activating the B cell lymphocytic leukemia.

In other study, miR-155 is overexpressed in the B cell lymphocytic leukemia [159]. The potential target for miR-155 is SHIP1. Expression of miR-155 causes the alteration of BCR response in signaling pathway via the modulation of SHIP1 expression in chronic lymphocytic leukemia. Scr homology-2 domain comprising the inositol 5-phosphatase is encoded by SHIP1. This phosphatase causes the inhibition of BCR signaling and surface immunoglobulin [158].

5.11 Pancreatic cancer

Pancreatic tumor is most of the time identified at the last stages when therapy does not save life. Li et al. characterize the pancreatic cancer stem cells (PCSCs) for the very first time [160].

In one study, there is overexpression of miR-1290 in pancreatic cancer. The direct target of miR-1290 is FoxA1 which has an effect on the transition of epithelial mesenchyma. The overexpression of miR-1290 results in the growth of cell and invasion [94].

In another study there is overexpression of miR-194 in pancreatic cancer. The target of miR-194 is DACH1 and results in the formation of the colony, the proliferation of cell, and migration (Table 22), so miR-194 causes the progression of the tumor [161].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-1290FoxA1Cell growth and invasion[94]
2miR-194DACH1Progression of tumor[161]

Table 22.

MicroRNAs activating the pancreatic cancer.

The growth and differentiation of the cell are regulated by LIN28, a protein that binds to the RNA [162]. The protein that is encoded by LIN28 is 25 kDa and has two binding sites for RNA: cold shock domain (CSD) and a pair of zinc fingers. In pancreatic cancer, the expression of LIN28 is increased which in turn suppresses the biosynthesis of family let-7 of microRNA (Figure 15). This family targets the genes involved in the growth and differentiation regulation [163]. This LIN28 causes the inhibition by binging to the loop present at the terminal region of let-7 family, so their processing is blocked [45, 46, 164]. This family is involved in the regulation of tumor by cyclin D1 (CCND1) inhibition [165, 166].

Figure 15.

miRNA and pancreatic cancer.

In one study there is downregulation of miR-145 in pancreatic cancer. The decreased expression of miR-145 is due to activation of the K-ras gene. Expression of miR-145 causes the inhibition of expression of insulin growth factor-1 receptors (Table 23). Its expression causes the downregulation of genes related to cancer (SET, MCM2, SPTBN1). These genes cause growth and carcinogenesis of pancreatic cancer [161].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1let-7 familycyclin D1 (CCND1)Regulation of tumor[166]
2miR-145K-rasGrowth and carcinogenesis[161]

Table 23.

MicroRNAs suppressing the pancreatic cancer.

5.12 Acute myeloid leukemia

In the myeloid leukemia, malignant blast cells are synthesized in comparison to mononuclear cells of healthy bone marrow [167]. In myeloid leukemia the hypermethylation of the DNA is involved in tumor suppression [168]. In one study, there is overexpression of miR-204 in acute myeloid leukemia. The target of miR-204 is MEIS1 and HOXA 10 genes which disturbs the differentiation of myeloid cells. Its overexpression causes tumorigenesis [169].

In another study, miR-125b (located on chromosome 1) is overexpressed in acute myeloid leukemia. The target of miR-125b is BCL2-antagonist/killer 1 (Bak1) which enhance the proliferation of AML cell and prevent the apoptosis [169].

In another study, miR-155 (located on chromosome 21) is overexpressed in the acute myeloid leukemia. This miR-155 is located in B cell integration cluster (BIC) gene. This BIC correlated to MYC to initiate lymphomas. Overexpression of miR-155 causes the inhibition of WEE1, a regulator of the cell cycle, and hMLH1, hMLH6, and hMLH4, the genes for mismatch repair (Table 24). The result of this inhibition is increased in mutation rate in progenitor and hematopoietic stem cells [169].

Sr. no.MicroRNAsPotential targetsFunction
1miR-204MEIS1 and HOXATumorigenesis
2miR-125bBak1Enhance proliferation and prevent apoptosis
3miR-155WEE1, hMLH1, hMLH6, and hMLH4Increase mutation rate in progenitor and hematopoietic stem cells

Table 24.

MicroRNAs activating the acute myeloid leukemia [169].

The known biomarker for the acute myeloid leukemia is miR-29b [167]. miR-29b causes the hypomethylation of the DNA. Sp1 transcriptional factor has the binding site for both miR-29b and DNMT1. In DNMT, it binds to its promoter and 3′UTR for miR-29b of Sp1 (specificity protein 1). Binding to the 3′UTR causes the reduced expression of Sp1, so DNMT (DNA methyltransferase) expression is also reduced (Figure 16). In acute myeloid leukemia, miR-29b results in the apoptosis when it directly targets the MCL (induced myeloid leukemia cell differentiation protein) [170]. So the expression of miR-29b is reduced in acute myeloid leukemia which leads to cancer progression as apoptosis has been decreased with reduced expression of miR-29b (Table 25).

Figure 16.

miRNA and acute myeloid leukemia.

Sr. no.MicroRNAsPotential targetsFunction
2miR-29bMCL proteinApoptosis

Table 25.

MicroRNAs suppressing the acute myeloid leukemia [170].

5.13 Ovarian cancer

In ovarian cancer, the biomarker that is used is miR-214 and it is upregulated in cancer. It binds to the 3′UTR region of phosphatase and tensin analog (PTEN) gene and causes its hypermethylation. So this is inactivated. The direct target of PTEN is Akt protein kinase B and mediates its activation by the help of PI4K3B [171]. Akt causes the downstream effects such as activation of glycogen synthase. So when PTEN is inhibited, it activates the expression of Akt. This miR-214 resists the cisplatin-mediated cell death, so it is antiapoptotic in nature (Figure 17). Cisplatin is an important factor in mediating cell death [172].

Figure 17.

miRNA and ovarian cancer.

In a study, there is overexpression of Hsa-miR-182 in ovarian cancer. The potential target of Hsa-miR-182 is forkhead box 3 (FOXO3) and forkhead box 1 (FOXO1) which promote the differentiation and inhibition of growth (acting as a tumor suppressor). These tumor suppressor genes are suppressed, and growth and proliferation of ovarian cell are increased (Table 26) [173].

Sr. no.MicroRNAsPotential targetsFunctionRef.
2Hsa-miR-182FOXO3 and FOXO1Increased proliferation and growth[173]

Table 26.

MicroRNAs activating the ovarian cancer.

In another study, there is downregulation of miR-200 family in ovarian cancer. The direct target of miR-200 is zinc finger E-box-binding homeobox 1 and 2 (ZEB1 and ZEB2). It prevents the EMT, metastasis, invasion, and migration of tumor cell. Interleukin-8 and CXCL1 (released from tumor epithelial cells) are also the target of miR-200 and prevent the angiogenesis of tumor cell [174].

In another study there is downregulation of miR-506 in ovarian cancer, so there is cell migration invasion of the cancer cell. When this miRNA is overexpressed, it causes the expression of E-cadherin and results in inhibition of cell invasion and migration and proliferation of ovarian cancer and, via targeting SNAI2 (E-cadherin transcriptional factor), prevents the EMT induction by TGF-β(Table 27). The miR-506 directly targets the CDK4/CDK6-FOXM1 axis and initiates the senescence [175].

Sr. no.MicroRNAsPotential targetsFunctionRef.
1miR-200ZEB1 and ZEB2Prevent the EMT, metastasis, invasion, and migration[174]
2miR-506SNAI2, CDK4/CDK6-FOXM1 axisInhibition of cell invasion and migration and proliferation; initiates the senescence[175]

Table 27.

MicroRNAs suppressing the ovarian cancer.


6. Conclusion

MicroRNAs (miRNAs) could be used as potential tool for early detection of cancer. It may upregulate or downregulate multiple targets through various mechanisms. It is upregulated as an oncogene (miRNA) and downregulated as a tumor suppressor. microRNA targets the PTEN, interferon (tumor suppressor genes), and also to the cell cycle along with the regulation of these genes [172]. MicroRNA is of vital importance because of its resistance to degradation and could be a potential candidate for clinical applications. However, its expression level can be screened in the serum/plasma (blood) by high-throughput sequencing technology. Further research for identification of novel microRNA will warrant the development of microRNA-related cancer prognosis [176, 177, 178, 179, 180].



miRISCmicroRNA-associated RNA-induced silencing complex
DGCR8DiGeorge syndrome chromosomal [or critical] region 8
EGFRepidermal growth factor receptor
FOXO1forkhead box protein O1
PTENphosphatase and tensin homolog
TPM1tropomyosin alpha-1 chain
SOX4SRY-related HMG-box
DNMTDNA methyltransferase
MCLinduced myeloid leukemia cell differentiation protein Mcl-1
PKBAkt (protein kinase B)


  1. 1. Hong L, Pan F, Jiang H, Zhang L, Liu Y, Cai C, et al. miR-125b inhibited epithelial-mesenchymal transition of triple-negative breast cancer by targeting MAP2K7. OncoTargets and Therapy. 2016;9:2639-2648
  2. 2. Mirnezami AH, Pickard K, Zhang L, Primrose JN, Packham G. MicroRNAs: Key players in carcinogenesis and novel therapeutic targets. European Journal of Surgical Oncology. 2009;35:339-347
  3. 3. Berezikov E, Guryev V, van de Belt J, Wienholds E, Plasterk RH, Cuppen E. Phylogenetic shadowing and computational identification of human microRNA genes. Cell. 2005;120:21-24
  4. 4. Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, et al. Identification of hundreds of conserved and nonconserved human microRNAs. Nature Genetics. 2005;37:766-770
  5. 5. Qu J, Li M, Zhong W, Hu C. Prognostic role of microRNA-25 in cancers: Evidence from a meta-analysis. International Journal of Clinical and Experimental Medicine. 2015;8:12921-12927
  6. 6. Kosaka N, Lguchi H, Ochiya T. Circulating microRNA in body fluid: A new potential biomarker for cancer diagnosis and prognosis. Cancer Science. 2010;101:2087-2092
  7. 7. Paranjape T, Slack FJ, Weidhaas JB. MicroRNAs: Tools for cancer diagnostics. Gut. 2009;58:1546-1554
  8. 8. Ghosh A, Ghosh A, Datta S, Dasgupta D, Das S, Ray S, et al. Hepatic miR-126 is a potential plasma biomarker for detection of hepatitis B virus infected hepatocellular carcinoma. International Journal of Cancer. 2016;138:2732-2744
  9. 9. Li C, Liu Z, Yang K, Chen X, Zeng Y, Liu J, et al. miR-133b inhibits glioma cell proliferation and invasion by targeting Sirt1. Oncotarget. 2016;7:36247-36254
  10. 10. Shah JS, Soon PS, Marsh DJ. Comparison of methodologies to detect low levels of Hemolysis in serum for accurate assessment of serum microRNAs. PLoS One. 2016;11:0153200
  11. 11. Pillai RS. MicroRNA function: Multiple mechanisms for tiny RNA. RNA. 2005;11(2):1753-1761
  12. 12. Lee RC, Feinbaum RL, Ambros V. TheC. elegansheterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843-854
  13. 13. Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism and function. Cell. 2004;116:281-297
  14. 14. Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nature Reviews Molecular Cell Biology. 2009;10:126-139
  15. 15. Lee YS, Dutta A. MicroRNAs in cancer. Annual Review of Pathology. 2009;4:199-227
  16. 16. Nishida-Aoki N, Ochiya T. Interactions between cancer cells and normal cells via miRNAs in extracellular vesicles. Cellular and Molecular Life Sciences. 2015;72:1849-1861
  17. 17. Zhou X, Ji G, Chen H, Jin W, Yin C, Zhang G. Clinical role of circulating miR-223 as a novel biomarker in early diagnosis of cancer patients. International Journal of Clinical and Experimental Medicine. 2015;9:16890-16898
  18. 18. Oliveto S et al. Role of microRNAs in translation regulation and cancer. World Journal of Biological Chemistry. 2017;8(1):45-56
  19. 19. Lee Y, Jeon K, Lee JT, Kim S, Kim VN. MicroRNA maturation: Stepwise processing and subcellular localization. EMBO Journal. 2002;21:4663-4670
  20. 20. Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, et al. MicroRNA genes are transcribed by RNA polymerase II. EMBO Journal. 2004;23:4051-4060
  21. 21. Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, et al. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425:415-419
  22. 22. Hammond SM, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in drosophila cells. Nature. 2000;404:293-296
  23. 23. El-Hefnawy T, Raja S, Kelly L, Bigbe WL, Kirkwood JM, Luketich JD, et al. Characterization of amplifiable, circulating RNA in plasma and its potential as a tool for cancer diagnostics. Clinical Chemistry. 2004;50:564-573
  24. 24. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology. 2007;9:654-659
  25. 25. Hayes N, Chayama K. MicroRNAs as biomarkers for liver disease and hepatocellular carcinoma. International Journal of Molecular Sciences. 2016;17:1-17
  26. 26. Yekta K, Shih IH, Bartel DP. MicroRNA-directed cleavage of HOXB8 mRNA. Science. 2004;304:594-596
  27. 27. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834-838
  28. 28. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proceedings of the National Academy of Sciences. 2006;103:2257-2261
  29. 29. Waldman SA, Terzic A. Translating MicroRNA discovery into clinical biomarkers in cancer. Journal of the American Medical Association. 2007;297:1923-1925
  30. 30. Chen CZ. MicroRNAs as oncogenes and tumor suppressors. The New England Journal of Medicine. 2005;353:1768-1771
  31. 31. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. A Cancer Journal for Clinicians. 2011;61:69-90
  32. 32. Tang J, Ahmad A, Sarkar FH. The role of microRNAs in breast cancer migration, invasion and metastasis. International Journal of Molecular Sciences. 2012;13:13414-13437
  33. 33. Qi L, Bart J, Tan LP, Platteel I, Sluis T, Huitema S, et al. Expression of miR-21 and its targets (PTEN, PDCD4, TM1) in flat epithelial atypia of the breast in relation to ductal carcinoma in situ and invasive carcinoma. BMC Cancer. 2009;9:163
  34. 34. Song B, Wang C, Liu J, Wang X, Lv L, Wei L, et al. MicroRNA-21 regulates breast cancer invasion partly by targeting tissue inhibitor of metalloproteinase 3 expression. Journal Experimental Clinical Cancer Reseaech. 2010;29(1):29
  35. 35. Jiang S, Zhang HW, Lu MH, He XH, Li Y, Gu H, et al. MicroRNA-155 functions as an OncomiR in breast cancer by targeting the suppressor of cytokine signaling 1 gene. Cancer Research. 2010;20(8):3119-3127
  36. 36. Zhang CM, Zhao J, Deng HY. MiR-155 promotes proliferation of human breast cancer MCF-7 cells through targeting tumor protein 53-induced nuclear protein 1. Journal of Biomedical Sciences. 2013;20:79
  37. 37. Kong W, He L, Coppola M, Guo J, Esposito NN, Coppola D, et al. MicroRNA-155 regulates cell survival, growth, and chemosensitivity by targeting FOXO3a in breast cancer. Journal of Biological Chemistry. 2010;285:17869-17879
  38. 38. Schooneveld EV, Wildiers H, Vergote I, Vermeulen PB, Dirix LY, Laere SJV. Dysregulation of microRNAs in breast cancer and their potential role as prognostic and predictive biomarkers in patient management. Breast Cancer Research. 2015;17:21
  39. 39. Huang GQ, Gumireddy K, Schrier M, le Sage C, Nagel R, Coukos G, et al. The microRNAs miR-373 and miR-520c promote tumour invasion and metastasis. Nature Cell Biology. 2008;10:202-210
  40. 40. Yan GR, Xu SH, Tan ZL, Liu L, He QY. Global identification of miR-373-regulated genes in breast cancer by quantitative proteomics. Proteomics. 2011;11:912-920
  41. 41. Ferracin M, Bassi C, Pedriali M, Pagotto S, D’Abundo L, Zagatti B, et al. miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression. Molecular Cancer. 2013;12:130
  42. 42. Feliciano A, Castellvi J, ArteroCastro A, Leal JA, Romagosa C, HernandezLosa J, et al. miR-125b acts as a tumor suppressor in breast tumorigenesis via its novel direct targets ENPEP, CK2-α, CCNJ, and MEGF9. PLoS One. 2013;8:e76247
  43. 43. Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. Journal of Biological Chemistry. 2007;282:1479-1486
  44. 44. Wang S, Huang J, Lyu H, Lee CK, Tan J, Wang J, et al. Functional cooperation of miR-125a, miR-125b, and miR-205 in entinostat-induced downregulation of erbB2/erbB3 and apoptosis in breast cancer cells. Cell Death & Disease. 2013;21(4):e556
  45. 45. Liu J, Mao Q, Liu Y, Hao X, Zhang S, Zhang J. Analysis of miR-205 and miR-155 expression in the blood of breast cancer patients. Chinese Journal of Cancer Research. 2013a;25:46-54
  46. 46. Liu T, Huang Y, Liu J, Zhao Y, Jiang L, Huang Q, et al. MicroRNA-122 influences the development of sperm abnormalities from human induced pluripotent stem cells by regulating TNP2 expression. Stem Cells and Development. 2013b;22:1839-1850
  47. 47. Jiang H, Wang P, Li X, Wang Q, Deng Z-B, Zhuang X, et al. Restoration of MiR-17/20a in Solid Tumor Cells Enhances the Natural Killer Cell Antitumor Activity by Targeting Mekk2. Cancer Immunology Research. 2014;2(8):789-799
  48. 48. Li Y, Hong F, Yu Z. Decreased expression of microRNA-206 in breast cancer and its association with disease characteristics and patient survival. The Journal of International Medical Research. 2013;41:596-602
  49. 49. Roy SS, Gonugunta VK, Bandyopadhyay A, Rao MK, Goodall GJ, Sun LZ, et al. Significance of PELP1/HDAC2/miR-200 regulatory network in EMT and metastasis of breast cancer. Oncogene. 2014;33:3707-3716
  50. 50. Xiang M, Birkbak NJ, Vafaizadeh V, Walker SR, Yeh JE, Liu S, Kroll Y, Boldin M, Taganov K, Groner B, Richardson AL, and Frank DA. STAT3 Induction of MiR-146b Forms a Feedback Loop to Inhibit the NF-κB to IL-6 Signaling Axis and STAT3-Driven Cancer Phenotypes. Science Signal. 2014;7(310):ra11
  51. 51. Png KJ, Halberg N, Yoshida M, Tavazoie SF. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature. 2012;481:190-194
  52. 52. Zhang S, Kim K, Jin UH, Pfent C, Cao H, Amendt B, et al. Aryl hydrocarbon receptor agonists induce microRNA-335 expression and inhibit lung metastasis of estrogen receptor negative breast cancer cells. Molecular Cancer Therapeutics. 2012;11:108-118
  53. 53. Augoff K, McCue B, Plow EF, Sossey-Alaoui K. miR-31 and its host gene lncRNA LOC554202 are regulated by promoter hypermethylation in triple-negative breast cancer. Molecular Cancer. 2012;11:5
  54. 54. Sossey-Alaoui K, Downs-Kelly E, Das M, Izem L, Tubbs R, Plow EF. WAVE3, an actin remodeling protein, is regulated by the metastasis suppressor microRNA, miR-31, during the invasion-metastasis cascade. International Journal of Cancer. 2011;129:1331-1343
  55. 55. Stenmark H. Rab GTPases as coordinators of vesicle traffic. Nature Reviews Molecular Cell Biology. 2009;10:513-525
  56. 56. Kelly EE, Horgan CP, McCaffrey MW. Rab11 proteins in health and disease. Biochemical Society Transactions. 2012;40:1360-1367
  57. 57. Palmieri D, Bouadis A, Ronchetti R, Merino MJ, Steeg PS. Rab11a differentially modulates epidermal growth factor-induced proliferation and motility in immortal breast cells. Breast Cancer Research and Treatment. 2006;100:127-137
  58. 58. Yang H, Yu J, Wang L, Ding D, Zhang L, Chu C, et al. miR-320a is an independent prognostic biomarker for invasive breast cancer. Oncology Letters. 2014;8:1043-1050
  59. 59. Schneider JG, Alosi JA, McDonald DE, McFadden DW. Pterostilbene inhibits lungs cancer through induction of apoptosis. Journal of Surgical Research. 2010;161:18-22
  60. 60. Morrow AA, Alipour MA, Bridges D, Yao Z, Saltiel AR, Lee JM. The lipid kinase PI4KIII beta is highly expressed in breast tumors and activates Akt in cooperation with Rab11a. Molecular Cancer Research. 2014;12:1492-1508
  61. 61. Yu J, Wang J, Zhang L, Yang H, Wang L, Ding D, et al. MicroRNA-320a inhibits breast cancer metastasis by targeting metadherin. Oncotarget. 2016;7(25):38612-38625
  62. 62. Peden AA, Schonteich E, Chun J, Junutula JR, Scheller RH, Prekeris R. The RCP-Rab11 complex regulates endocytic protein sorting. Molecular Biology of the Cell. 2004;15:3530-3541
  63. 63. Gelsi-Boyer V, Orsetti B, Cervera N, Finetti P, Sircoulomb F, Rouge C, et al. Comprehensive profiling of 8p11-12 amplification in breast cancer. Molecular Cancer Research. 2005;3:655-667
  64. 64. Zhang J, Liu X, Datta A, Govindarajan K, Tam WL, Han J, et al. RCP is a human breast cancer-promoting gene with Ras-activating function. The Journal of Clinical Investigation. 2009;119:2171-2183
  65. 65. Caswell PT, Chan M, Lindsay AJ, McCaffrey MW, Boettiger D, Norman JC. Rab-coupling protein coordinates recycling of alpha5beta1 integrin and EGFR1 to promote cell migration in 3D microenvironments. Journal of Cell Biology. 2008;183:143-155
  66. 66. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics. A Cancer Journal for Clinicians. 2014;64:104-117
  67. 67. Smith RA, Eschenbach ACV, Wender R, Levin B, Byers T, Rothenberger D, et al. American Cancer Society guidelines for the early detection of cancer: Update of early detection guidelines for prostate, colorectal, and endometrial cancers. Also: Update 2001—Testing for early lung cancer detection. A Cancer Journal for Clinicians. 2001;51:38-75
  68. 68. O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435:839-843
  69. 69. Sokolova V, Fiorino A, Zoni E, Crippa E, Reid JF, Gariboldi M, et al. The effects of miR-20a on p21: Two mechanisms blocking growth arrest in TGF-β-responsive colon carcinoma. Journal of Cellular Physiology. 2015;230:3105-3114
  70. 70. Diosdado B, van de Wiel MA, Terhaar Sive Droste JS, Mongera S, Postma C, Meijerink WJHJ, et al. MiR-17-92 cluster is associated with 13q gain and c-myc expression during colorectal adenoma to adenocarcinoma progression. British Journal of Cancer. 2009;101:707-114
  71. 71. Luo X, Burwinkel B, Tao S, Brenner H. MicroRNA signatures: Novel biomarker for colorectal cancer. American Association for Cancer Research. 2011;20:1272-1286
  72. 72. Xu T, Jing C, Shi Y, Miao R, Peng L, Kong S, et al. MicroRNA-20a enhances the epithelial-to-mesenchymal transition of colorectal cancer cells by modulating matrix metalloproteinases. Experimental and Therapeutic Medicine. 2015a;10(10):683-10688
  73. 73. Xu Y, Zhao S, Cui M, Wang Q. Down-regulation of microRNA-135b inhibited growth of cervical cancer cells by targeting FOXO1. International Journal of Clinical and Experimental Pathology. 2015b;8:10294-10304
  74. 74. Zhang GJ, Li Y, Zhou H, Xiao HX, Zhou T. miR-20a is an independent prognostic factor in colorectal cancer and is involved in cell metastasis. Molecular Medicine Reports. 2014;10:283-291
  75. 75. Wang J, Sun L, Myeroff L, Wang X, Gentry LE, Yang J, et al. Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. The Journal of Biological Chemistry. 1995;270:22044-22049
  76. 76. Zhong CY, Sun WW, Ma Y, Zhu H, Yang P, Wei H, et al. Microbiota prevents cholesterol loss from the body by regulating host gene expression in mice. Scientific Reports. 2015;5:10512
  77. 77. Schaubeck M, Clavel T, Calasan J, Lagkouvardos I, Haange SB, Jehmlich N, et al. Dysbiotic gut microbiota causes transmissible Crohn’s disease-like ileitis independent of failure in antimicrobial defence. Gut. 2015;65:225-237
  78. 78. Yau TO, Wu CW, Tang C, Chen Y, Fang J, Dong Y, et al. microRNA-20a in human faeces as a non-invasive biomarker for colorectal cancer. Oncotarget. 2016;7:1559-1568
  79. 79. Siemens H, Jackstadt R, Hunten S, Kaller M, Menssen A, Gotz U, et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle. 2011;10(24):4256-4271
  80. 80. Cekaite L, Eide PW, Lind GE, Skotheim RI, Lothe RA. MicroRNAs as growth regulators, their function and biomarker status in colorectal cancer. Oncotarget. 2016;7(6):6476-6505
  81. 81. He L, He X, Lim LP, De Stanchina E, Xuan Z, Liang Y, et al. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447(7148):1130-1134
  82. 82. Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nature Review Cancer. 2014;14(5):359-370
  83. 83. Davalos V, Moutinho C, Villanueva A, Boque R, Silva P, Carneiro F, et al. Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. Oncogene. 2012;31(16):2062-2074
  84. 84. Chen L, Zheng J, Zhang Y, Yang L, Wang J, Ni J, et al. Tumor-specific expression of microRNA-26a suppresses human hepatocellular carcinoma growth via cyclin-dependent and -independent pathways. Molecular Therapy. 2011;19(8):1521-1528
  85. 85. Paterson EL, Kazenwadel J, Bert AG, Khew- Goodall Y, Ruszkiewicz A, Goodall GJ. Down- regulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. Neoplasia. 2013;15(2):180-191
  86. 86. Oster B, Linnet L, Christensen LL, Thorsen K, Ongen H, Dermitzakis ET, et al. Group Colofol Steering. Laurberg S et al. Non-CpG island promoter hypomethylation and miR-149 regulate the expression of SRPX2 in colorectal cancer. International Journal of Cancer. 2013;132(10):2303-2315
  87. 87. El-Murr N, Abidi Z, Wanherdrick K, Svrcek M, Gaub MP, Flejou JF, et al. MiRNA genes constitute new targets for microsatellite instability in colorectal cancer. PLoS One. 2012;7(2):e31862
  88. 88. Nandakumar A, Ramnath T, Chaturvedi M. The magnitude of cancer cervix in India. Indian Journal of Medical Research. 2009;130:219-221
  89. 89. Denny L. Cervical cancer: Prevention and treatment. Discovery Medicine. 2012;14:125-131
  90. 90. Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G, Mayrand MH, et al. Overview of human papillomavirus-based and other novel options for cervical cancer screening in developed and developing countries. Vaccine. 2008;26(supplement 10):K29-K41
  91. 91. Díaz-González SM, Deas J, Benítez-Boijseauneau O, Gómez-Cerón C, Bermúdez-Morales VH, Rodríguez-Dorantes M, et al. Utility of microRNAs and siRNAs in cervical carcinogenesis. BioMed Research International. 2015;2015:374924
  92. 92. Zhao Q, Zhai XY, Liu HQ, Shi YA, Li XB. MicroRNA-491-5p suppresses cervical cancer cell growth by targeting Htert. Oncology Reports. 2015;34:979-986
  93. 93. Deng B, Zhang Y, Zhang S, Wen F, Miao Y, Guo K. MicroRNA-142-3p inhibits cell proliferation and invasion of cervical cancer cells by targeting FZD7. Tumour Biology. 2015;36:8065-8073
  94. 94. Li XR, Chu HJ, Lv T, Wang L, Kong SF, Dai SZ. miR-342-3p suppresses proliferation, migration and invasion by targeting FOXM1 in human cervical cancer. FEBS Letters. 2014;588:3298-3307
  95. 95. Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005;24:7410-7425
  96. 96. Huang H, Regan KM, Lou Z, Chen J, Tindall DJ. CDK2-dependent phosphorylation of FOXO1 as an apoptotic response to DNA damage. Science. 2006;314:294-297
  97. 97. Hou T, Ou J, Zhao X, Huang X, Huang Y, Zhang Y. MicroRNA-196a promotes cervical cancer proliferation through the regulation of FOXO1 and p27Kip1. British Journal of Cancer. 2014;110:1260-1268
  98. 98. Long MJ, Wu FX, Li P, Liu M, Li X, Tang H. MicroRNA-10a targets CHL1 and promotes cell growth, migration and invasion in human cervical cancer cells. Cancer Letters. 2012;324(2):186-196
  99. 99. Sekuklu SD, Donoghue MTA, Spillane C. miR-21 as a key regulator of oncogenic processes. Biochemical Society Transactions. 2009;37(4):918-925
  100. 100. Kota J, Chivukula RR, Donnell KA, Wentzel EA, Montgomery LC, Hwang HW, et al. Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model. Cell. 2009;137:1005-1017
  101. 101. Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C, et al. Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Research. 2007;67:2456-2468
  102. 102. Kim HS, Lee KS, Bae HJ, Eun JW, Shen Q, Park SJ, et al. MicroRNA-31 functions as a tumor suppressor by regulating cell cycle and epithelial-mesenchymal transition regulatory proteins in liver cancer. Oncotarget. 2015;6(10):8089-8102
  103. 103. Drakaki A, Hatziapostolou M, Polytarchou C, Vorvis C, Poultsides GA, Souglakos J, et al. Functional microRNA high throughput screening reveals miR-9 as a central regulator of liver oncogenesis by affecting the PPARA- CDH1 pathway. BMC Cancer. 2015;15:542
  104. 104. Pang F, Zha R, Zhao Y, Wang Q, Chen D, Zhang Z, et al. MiR-525-3p enhances the migration and invasion of liver cancer cells by downregulating ZNF395. PLoS One. 2014;9(3):e90867
  105. 105. Gronberg H. Prostate cancer epidemiology. Lancet. 2003;361:859-864
  106. 106. Meeker AK, Hicks JL, Platz EA, March GE, Bennett CJ, Delannoy MJ. Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis. Cancer Research. 2002;62:6405-6409
  107. 107. Dong JT, Isaacs WB, Isaacs JT. Molecular advances in prostate cancer. Current Opinion in Oncology. 1997;9:101-107
  108. 108. Wang JC, Begin LR, Berube NG, Chevalier S, Aprikian AG, Gourdeau H, et al. Down-regulation of CD9 expression during prostate carcinoma progression is associated with CD9 mRNA modification. Clinical Cancer Research. 2007;13:2354-2361
  109. 109. Yaman AF, Kovancilar M, Dizdar Y, Darendeliler E, Holdenrieder S, Dalay N. Investigation of miR-21, miR-141, and miR-221 in blood circulation of patients with prostate cancer. Tumor Biology. 2011;32:583-588
  110. 110. Kim WT, Kim WJ. MicroRNAs in prostate cancer. Prostate International. 2013;1:3-9
  111. 111. Massard C, Fizazi K. Targeting continued androgen receptor signaling in prostate cancer. Clinical Cancer Research. 2011;17:3876-3883
  112. 112. Waltering KK, Porkka KP, Jalava SE, Urbanucci A, Kohonen PJ, Latonen LM. Androgen regulation of micro-RNAs in prostate cancer. Prostate. 2011;71:604-614
  113. 113. Lewis H, Lance R, Troyer D, Beydoun H, Hadley M, Orians J, et al. miR-888 is an expressed prostatic secretions-derived microRNA that promotes prostate cell growth and migration. Cell Cycle. 2014;13(2):227-239
  114. 114. Saini S, Majid S, Dahiya R. Diet, MicroRNAs and Prostate Cancer. Pharmaceutical Research. 2010;27(6):1014-1026
  115. 115. Travis WD, Brambilla E, Harris CC, Muller-Hermelink HK, editors. World Health Organization Classification of Tumours, Pathology and Genetics: Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2004. pp. 12-15
  116. 116. Minna JD, Roth JA, Gazdar AF. Focus on lung cancer. Cancer Cell. 2002;1:49-52
  117. 117. Yanaihara N, Caplen E, Bowman E, Seike M, Kumamoto K, Yi M, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006;9:189-198
  118. 118. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120:635-647
  119. 119. Eberharter A, Becker PB. Histone acetylation: A switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Reports. 2002;3:224-229
  120. 120. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nature Reviews Genetics. 2002;3:415-428
  121. 121. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE, et al. A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. The New England Journal of Medicine. 2005;353:1793-1801
  122. 122. Qi J, Mu D. MicroRNAs and lung cancers: from pathogenesis to clinical implications. Front Medicine. 2012;6(2):134-155
  123. 123. Zhang JG, Wang JJ, Zhao F, Liu Q, Jiang K, Yang GH. MicroRNA-21 (miR-21) represses tumor suppressor PTEN and promotes growth and invasion in non-small cell lung cancer (NSCLC). Clinica Chimica Acta. 2010;411(11-12):846-852
  124. 124. Lize M, Klimke A, Dobbelstein M. MicroRNA-449 in cell fate determination. Cell Cycle. 2011;10(17):2874-2882
  125. 125. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. Helicobacter pylori infection and the development of gastric cancer. The New England Journal of Medicine. 2001;345:784-789
  126. 126. Ju HR, Jung U, Sonn CH, Yoon SR, Jeon JH, Yang Y, Lee KN, Choi I. Aberrant signaling of TGF-beta1 by the mutant Smad4 in gastric cancer cells. Cancer Letters 2003;196:197-206
  127. 127. Park K, Kim SJ, Bang YJ, Park JG, Kim NK, Roberts AB, et al. Genetic changes in the transforming growth factor beta (TGFbeta) type II receptor gene in human gastric cancer cells: Correlation with sensitivity to growth inhibition by TGF-beta. Proceedings of the National Academy of Sciences. 1994;91:8772-8776
  128. 128. Kim YK, Kim VK. Processing of intronic microRNAs. EMBO Journal. 2007;26:775-783
  129. 129. Blow JJ, Hodgson B. Replication licensing—Defining the proliferative state. Trends in Cell Biology. 2002;12:72-78
  130. 130. Mattioli E, Vogiatzi P, Sun A, Abbadessa G, Angeloni G, D’Ugo D, et al. Immunohistochemical analysis of pRb2/p130, VEGF, EZH2, p53, p16(INK4A), p27(KIP1), p21(WAF1), Ki-67 expression patterns in gastric cancer. Journal of Cellular Physiology. 2007;210:183-191
  131. 131. Brink VD, Offerhaus GJ. The morphogenetic code and colon cancer development. Cancer Cell. 2007;11:109-117
  132. 132. Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, Martino ID, et al. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008;13:272-286
  133. 133. Ohgushi M, Kuroki S, Fukamachi H, O’Reilly LA, Kuida K, Strasser A, et al. Transforming growth factor beta-dependent sequential activation of Smad, Bim, and caspase-9 mediates physiological apoptosis in gastric epithelial cells. Molecular and Cell Biology. 2005;25:10017-10028
  134. 134. Gross A, McDonnell JM, Korsmeyer SJ. BCL-2 family members and the mitochondria in apoptosis. Genes & Development. 1999;13:1899-1911
  135. 135. Lim JY, Yoon SO, Seol S-Y, Hong SW, Kim JW, Choi SH, et al. Overexpression of miR- 196b and HOXA10 characterize a poor-prognosis gastric cancer subtype. World Journal of Gastroenterology. 2013;19(41):7078-7088
  136. 136. Wu C, Li M, Hu C, Duan H. Clinical significance of serum miR-223, miR-25 and miR-375 in patients with esophageal squamous cell carcinoma. Molecular Biology Reports. 2014a;41(3):1257-1266
  137. 137. Wu H-H, Lin W-C, Tsai KW. Advances in molecular biomarkers for gastric cancer: miRNAs as emerging novel cancer markers. Expert Reviews in Molecular Medicine. 2014b;16:e1
  138. 138. Shin JY, Kim YI, Cho SJ, Lee MK, Kook MC, Lee JH, et al. MicroRNA 135a suppresses lymph node metastasis through down-regulation of ROCK1 in early gastric cancer. PLoS One. 2014;9:e85205
  139. 139. Cookson MS, Herr HW, Zhang ZF, Soloway S, Sogani PC, Fair WR. The treated natural history of high risk superficial bladder cancer: 15-year outcome. Journal of Urology. 1997;158:62-67
  140. 140. Dyrskjot L, Ostenfeld MS, Bramsen JB, Silahtaroglu AN, Lamy P, Ramanathan R, et al. Genomic profiling of microRNAs in bladder cancer: miR-129 is associated with poor outcome and promotes cell death in vitro. Cancer Research. 2009;69:4851-4860
  141. 141. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133:647-658
  142. 142. Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). Journal of Biological Chemistry. 2007;282:14328-14336
  143. 143. Liao R, Sun J, Zhang L. MicroRNAs play a role in the development of human hematopoietic stem cells. Journal of Cellular Biochemistry. 2008;104:805-817
  144. 144. Aaboe M, Birkenkamp-Demtroder K, Wiuf C. SOX4 expression in bladder carcinoma: Clinical aspects and in vitro functional characterization. Cancer Research 2006;66:343-442
  145. 145. Feng Y, Liu J, Kang Y, He Y, Liang B, Yang P, et al. miR-19a acts as an oncogenic microRNA and is up-regulated in bladder cancer. Journal of Experimental Clinical Cancer Research. 2014;33(1):67
  146. 146. Yu G, Yao W, Xiao W, Li H, Xu H, Lang B. MicroRNA-34a functions as an anti-metastatic microRNA and suppresses angiogenesis in bladder cancer by directly targeting CD44. Journal of Experimental Clinical Cancer Research. 2014;33(1):779
  147. 147. Rooj AK, Mineo M, Godlewski J. MicroRNA and extracellular vesicles in glioblastoma: Small but powerful. Brain Tumor Pathology. 2016;33:77-88
  148. 148. Cheng AM, Byrom MW, Shelton J, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Research. 2005;33:1290-1297
  149. 149. Chan JA, Krichevsky AM, Kosik K. Glioblastoma cells MicroRNA-21 is an antiapoptotic factor in human. Cancer Research. 2005;65:6029-6033
  150. 150. Brower JV, Clark PA, Lyon W, Kuo JS. MicroRNAs in cancer: glioblastoma and glioblastoma cancer stem cells. Neurochemistry International. 2014;77:68-77
  151. 151. Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, et al. microRNA-7 Inhibits the Epidermal Growth Factor Receptor and the Akt Pathway and Is Down-regulated in Glioblastoma. Cancer Research. 2008;68:10
  152. 152. Calin GA, Liu CG, Sevignani C, Ferracin M, Felli N, Dumitru CD, et al. MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias. Proceedings of the National Academy of Sciences of the United States of America. 2004;101:11755-11760
  153. 153. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America. 2002;99:15524-15529
  154. 154. Oscier DG, Gardiner A, Mould SJ, Glide S, Davis ZA, Ibbotson RE, et al. Multivariate analysis of prognostic factors in CLL: Clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood. 2002;100:1177-1184
  155. 155. Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clinical Cancer Research. 2002;8:1178-1184
  156. 156. Balatti V, Pekarky Y, Croce CM. Role of microRNA in chronic lymphocytic leukemia onset and progression. Journal of Hematology Oncology. 2015;8:12
  157. 157. Xiao C, Srinivasan L, Calado DP, Patterson HC, Zhang B, Wang J, et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nature Immunology. 2008;9:405-414
  158. 158. Balatti V, Acunzo M, Pekarky Y, Croce CM. Novel mechanisms of regulation of miRNAs in CLL. Trends Cancer. 2016;2(3):134-143
  159. 159. Fulci V, Chiaretti S, Goldoni M, Azzalin G, Carucci N, Tavolaro S. Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood. 2007;109(11):4944-4951
  160. 160. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Research. 2007;67:1030-1037
  161. 161. Li Y, Sarkar FH. MicroRNA Targeted Therapeutic Approach for Pancreatic Cancer. International Journal of Biological Sciences. 2016;12(3):326-337
  162. 162. Lei XX, Xu J, Ma W, Qiao C, Newman MA, Hammond SM, et al. Determinants of mRNA recognition and translation regulation by Lin28. Nucleic Acids Research. 2012;40:3574-3584
  163. 163. Peng S, Chen LL, Lei XX, Yang L, Lin H, Carmichael GG, Huang Y. Genome-wide studies reveal that Lin28 enhances the translation of genes important for growth and survival of human embryonic stem cells. Stem Cells. 2011;29:496-504
  164. 164. Qin W, Ren Q, Liu T, Huang Y, Wang J. MicroRNA-155 is a novel suppressor of ovarian cancer-initiating cells that targets CLDN1. FEBS Letters. 2013;587:1434-1439
  165. 165. Qiu C, Ma Y, Wang J, Peng S, Huang Y. Lin28-mediated post-transcriptional regulation of Oct4 expression in human embryonic stem cells. Nucleic Acids Research. 2010;38:1240-1248
  166. 166. Shao Y, Zhang L, Cui L, Lou W, Wang D, Lu W, et al. LIN28B suppresses microRNA let-7b expression to promote CD44+/LIN28B+ human pancreatic cancer stem cell proliferation and invasion. American Journal of Cancer Research. 2015;5:2643-2659
  167. 167. Garzon R, Liu S, Fabbri M, Liu Z, Heaphy CEA, Callegari E, et al. MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood. 2009;113:6411-6418
  168. 168. Toyota M, Kopecky KJ, Toyota MO, Jair KW, Willman CL, Issa JP. Methylation profiling in acute myeloid leukemia. Blood. 2001;97:2823-2829
  169. 169. Yeh CH, Moles R, Nicot C. Clinical significance of microRNAs in chronic and acute human leukemia. Molecular Cancer. 2016;15(1):37
  170. 170. Garzon R, Pichiorri F, Marcucci G, Kornblau S, Andreeff M, Croce C. MicroRNA-29b targets MCL-1 and is down-regulated in chemotherapy-resistant acute myeloid leukemia (AML). Blood. 2007;110:717
  171. 171. Testa JR, Bellacosa A. AKT play a central role in tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:10983-10985
  172. 172. Yang H, Kong W, He L, Zhao JJ, O’Donnell JD, Wang J, et al. MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Research. 2008;68:425-433
  173. 173. Delfino KR, Rodriguez-Zas SL. Transcription Factor-MicroRNA-Target Gene Networks Associated with Ovarian Cancer Survival and Recurrence. PLoS One. 2013;8(3):e58608
  174. 174. Kinose Y, Sawada K, Nakamura K, Kimura T. The Role of MicroRNAs in Ovarian Cancer. Biomed Research International. 2014;2014:249393
  175. 175. Liu G, Sun Y, Ji P, Li X, Cogdell D, Yang D, et al. MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. The Journal of Pathology. 2014;233(3):308-318
  176. 176. Baek D, Villen J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455:64-71
  177. 177. Chen L, Bourguignon LY. Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells. Molecular Cancer. 2014;13:52
  178. 178. Mei M, Ren Y, Zhou X, Yuan XB, Han L, Wang GX, et al. Downregulation of miR-21 enhances chemotherapeutic effect of taxol in breast carcinoma cells. Technology in Cancer Research & Treatment. 2010;9:77-86
  179. 179. Zhou M, Liu Z, Zhao Y, Ding Y, Liu H, Xi Y, et al. MicroRNA-125b confers the resistance of breast cancer cells to paclitaxel through suppression of pro-apoptotic Bcl-2 antagonist killer 1 (Bak1) expression. The Journal of Biological Chemistry. 2010;285:21496-21507
  180. 180. Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Research;65:9628-9632

Written By

Ayesha Siddiqua, Sumaira Kousar, Amer Jamil, Riaz Tabassum, Tariq Mehmood and Nusrat Shafiq

Submitted: August 26th, 2018 Reviewed: October 9th, 2019 Published: February 13th, 2020