There are several miRNA clusters whose expression is altered contributing to the induction of EMT in different cancer conditions. For example, the miR-200c/141 cluster promotes EMT in breast cancer by targeting Homeodomain Interacting Protein Kinase 1 (HIPK1) and by activating CTNNB1 (29). MiR-221/222 promotes EMT in breast cancer by targeting Phosphatase and Tensin Homolog (PTEN), Suppressor of Cytokine Signaling 1(SOCS1), Cyclin-Dependent Kinase Inhibitor 1B (CDKN1B) and Notch Receptor 3 (NOTCH3) (30–32). Similarly, miR-183/182 activates EMT in breast cancer by targeting Growth Hormone Receptor (GHR) (33). MiR-216/217 induces EMT by targeting PTEN and SMAD Family Member 7 (SMAD7), resulting in the activation of PI3K/AKT signaling and sorafenib resistance in liver cancer (34). MiR-17/92 cluster modulates NF-kB signaling via targeting of TNF Receptor Associated Factor 3 (TRAF3) in gastric cancer to induce EMT (35) (Figure 2).

Figure 2

miRNA Cluster regulates EMT pathway via targeting different genes and associated signaling pathways.

Several studies have shown the inhibition of EMT by miRNA clusters. For instance, miR-15a/16 inhibits EMT in prostate cancer by suppressing TGF-β (36). MiR-200c/141 inhibits EMT in colon and lung cancer by targeting Achaete-Scute Family BHLH Transcription Factor 2 (ASCL2) and Forkhead Box F2 (FOXF2) respectively (37, 38). FOXF2 is also inhibited by the miR-183/182 cluster in colon cancer (37). MiR-17/92 inhibited EMT by downregulation of CyclinD1 (CCND1), Slingshot Protein Phosphatase 1 (SSH1), LIM Domain Kinase 1 (LIMK1), Fibroblast Growth Factor 4 (FGFD4) and RhoGTPase (39) (Tables 1 - 2).

Snail Family Transcriptional Repressor 2 (SNAIL2), commonly known as the SLUG is located at 8q11.21. SLUG is overexpressed and amplified in numerous cancers is reported to promote cell migration, invasion, metastasis, cell cycle progression and resistance to apoptosis (52–57). SLUG is a transcription factor belonging to the zinc finger family induces transcriptional repression of CDH1 and is anti-apoptotic in nature. Highly aggressive tumors show overexpression and enhanced activity of SLUG. Both SNAIL and SLUG promote invasion and metastasis by altering the expression of CDH1 and VIM (58). They inhibit CDH1 by binding to the E-box sequences present in its promoter region (59). Further, SLUG is also capable of downregulating Claudin-1 (CLDN1) in Madin-Darby canine kidney (MDCK) cells (60). SLUG induces cell migration and invasion via TGF-β signaling (61). SLUG utilizes the SNAG domain to suppress target gene expression by recruiting histone deacetylases. Elevated SLUG expression is connected to CDH1 downregulation, induction of EMT, advanced tumor grade, lymph node metastasis and poor survival (62).

SLUG participates in TWIST1 induced EMT pathways by repressing the transcription of CDH1 (52, 63). Many of the miRNA clusters downregulate SLUG expression and inhibit EMT. For instance, miR-17/92 cluster expression is correlated with inhibition of SLUG and induction of CDH1 with inhibitory effect on EMT (39). MiR-34, a member of the miR-34b/c cluster acts as a tumor suppressor and inhibitor of EMT by targeting SLUG (64). MiR-96/183 promotes the expression of key EMT inducers such as ZEB1, ZEB2, SNAIL2, MMP2, and MMP9 by suppressing the breast cancer metastasis suppressor 1-like (BRMS1L) (33). MiR-183/182 is another miRNA cluster that promotes EMT by promoting the expression of mesenchymal genes and EMT-TFs such as SNAIL, and SLUG (49, 65). In colorectal cancer, miR-182 targets FOXF2 and induces growth and migration of cancer cells (66). MiR-182, along with miR-203, acts as an inducer of EMT by targeting SLUG expression in prostate cancer (67). MiR-183 and miR-96 are a suppressor of EMT by targeting ZEB1, SLUG, Integrin beta 1 (ITGB1), and Kruppel-like factor 4 (KLF4) (49). Taken together, SLUG is an important inducer of EMT whose expression is upregulated in cancer via altered expression of miRNA clusters.

Snail Family Transcriptional Repressor 1 (SNAIL1) is a pro-EMT gene overexpressed in many metastatic cancers promoting cell survival and migration. SNAIL, via its N-terminal SNAG domain, interacts with and recruits co-repressors and repressors to the promoter region of CDH1 thereby promoting EMT. Pro-EMT signaling pathways [RTKs, TGF-β, Notch, Wnt, TNF-α, and bone morphogenetic protein 2 (BMP)] along with tumor microenvironment are reported to promote EMT by inducing SNAIL expression. From the clinical perspective, SNAIL expression levels are correlated with tumor grade, metastasis to lymph node and clinical outcome in metastatic cancer. Moreover, SNAIL overexpression is reported to induce metabolic reprogramming and to promote drug resistance, recurrence, and metastasis (68–70).

Emerging evidence suggests crosstalk between miRNA cluster and SNAIL during EMT program. MiR-23a/24/27a located at 19p13.12 is regulated through MAPK and TGF-β signaling. MiR-23a-3p inhibits EMT via TGF-β/Akt/MAPK/Snail axis (71). In bladder cancer, miR-323a-3p/MET proto-oncogene (MET)/SMAD3/SNAIL axis is reported to regulate EMT (72). MiR-106b/25 cluster enhances non-small cell lung cancer (H1299) cell migration and invasion via targeting of F-box and WD repeat domain containing 11 (β-TRCP2) by enhancing the expression of SNAIL (73). MiR-206 of miR-206/133b cluster targets MET and PI3k/Akt/mTOR pathways and suppresses EMT (74). MiR-183 cluster consists of miRs-183, -96 and -182, and is overexpressed in numerous cancers. MiR-182 directly targets metastasis suppressor 1 (MTSS1) and induces the proliferation of breast cancer cells (75). As a member of the miR-181 family, miR-181a is associated with cell proliferation and invasion in multiple cancer. MiR-181a is reported as an inducer of EMT in prostate cancer by targeting TGF-β induced factor homeobox (TGIF2) (76). In breast cancer, miR-181b-3p acts as a promoter of EMT via SNAIL stabilization by targeting Tyrosine 3-Monooxygenase/Tryptophan 5-Monooxygenase Activation Protein Gamma (77). The role of Smad2/3/4-dependent pathway in EMT is reported in gastric cancer. Smad2/3/4 pathway induces the expression of miRNA-181b and targets TIMP metallopeptidase inhibitor 3 (TIMP3) to promote EMT and metastasis (78). MiR-200 family consists of anti-EMT miRNAs their expression is important to determine the epithelial phenotypes in cancer. MiR-200 family activates CDH1 expression by targeting ZEB1 and ZEB2 (65). The down-regulation of miR-200 is reported to enhance the expression of SNAIL and SLUG (79). Studies have shown that miR-34/SNAIL/miR-200/ZEB1 can regulate EMT dynamics (80). Inhibition of miR-200c/141 results in the upregulation of VIM and SNAIL in breast cancer stem cells (29). MiR-424/503 is another miRNA cluster with tumor suppressive function, the downregulation of which is correlated with resistance to chemotherapy in breast cancer (81). Thus, taken together, miRNA clusters are important regulators of SNAIL expression.

TWIST1 and TWIST2 belong to the basic helix-loop-helix (bHLH) transcription factor family. They promote EMT and enhance the motility and dissemination of cancer cells (82). In benign tumors activation of TWISTs favors malignant transformation via inhibition of apoptosis and senescence pathways. TWIST proteins with their bHLH motif recognize E-box and can act as an activator or repressor of target gene expression (83). TWIST overexpression is correlated with aggressive cancer, poor prognosis, metastasis, and poor survival. Pathways such as Wnt, IGF, EGF, TNF-α, IL-17 either induce TWIST expression or stabilize via their target genes (NF-κB, STAT3, and c-MYC) (16, 84–87). Cytokines, chemokines (IL6, EGF) and hypoxia are reported to induce the expression of TWISTs to promote EMT (17, 86, 88).

Many miRNA clusters participate in the TWIST induced EMT program. MiR-15a-3p and miR-16-1-3p belonging to the miR-15 cluster, are reported to inhibit invasion and metastasis of gastric cancer cells by TWIST1 repression (89). TWIST1 is also reported to regulate the expression of miRNA clusters. An example includes the regulation of miR-199a/214 cluster expression by TWIST1 during development (90). In breast cancer, it induces EMT via the miR-373-TXNIP-HIF1α-TWIST signaling axis (91). Both up and down-regulation of the members of the miR-199a/214 cluster are reported to contribute to EMT in cancer (92). Transcription of miR-214 is regulated by TWIST1 and ZEB1 (93). MiR-424(322)/503 is another miRNA cluster linked with TWIST. The upregulation of miR-424 in TWIST1 or SNAI1-induced EMT is reported (94). MiR-106b/25 is an oncogenic cluster in many cancers and has two paralogs in humans namely miR-106b/25 and miR-17/92. MiR-106b is a pro-metastatic miRNA cluster in hepatocellular carcinoma cells (95). Hypoxia is reported to induce EMT via controlling miRNA cluster expression. For instance, Twist/miR-214/CDH1 interaction is promoted by hypoxia in the induction of renal tubular EMT (96). MiR-524-5p is a member of the chromosome19 miRNA cluster (C19MC) which directly targets TWIST1 to inhibit EMT (97). Taken together, miRNA clusters and the TWIST axis could be a potential target in cancer therapy.

ZEB1 and ZEB2 are located in short arm of chromosome 10 and 2 belonging to zinc finger E-box binding homeobox (ZEB) family. ZEB family induces EMT most often through activating genes such as CDH2, Vitronectin (VTN) and MMPs. ZEB induced EMT also shows the downregulation of CDH1, Claudins, ZO-1, and plakophilins. ZEBs are commonly known as Smad interacting protein 1 (SIP1) consisting of two zinc finger clusters and a central homeodomain (98). ZEB induced EMT also involves miRNA clusters. MiR-200c/miR-141 targets ZEB1 and ZEB2 thereby inhibiting migration and EMT in head and neck cancer cells (99). Loss of miR-200c/miR-141cluster is important for lymph endothelial invasiveness in 5-fluorouracil resistant cells (100). By targeting members of C terminal binding protein (CtBP)/ZEB complex, miR-141-200c cluster regulates EMT (101). MiR-143/145 is downregulated in multiple cancers and is an EMT and metastatic suppressor. In response to stress, serum starvation or anti-cancer agents, p53 can activate this cluster. This miRNA cluster is suppressed by activated Ras via binding to Ras-responsive element-binding protein (RREB1) (102). MiR-132 suppresses lung cancer cell migration by targeting ZEB2 (103). MiRNA-23b/27b/24 is an oncogenic miRNA cluster that promotes metastasis of breast cancer by suppressing Prosaposin (PSAP) (104). MiR-23b targets Protein Tyrosine Kinase 2 Beta (PYK2β) and suppresses EMT and metastasis in hepatocellular carcinoma (105). MiR23b targets ZEB1, and acts as a tumor suppressor preventing migration and invasion of bladder cancer cells (106). MicroRNA-200/ZEB/CDH1 and miR-200/ZEB/TGF-β axis are also reported in cancer (107, 108). MiR-544 is a member of the miR-379/miR-544 cluster and highly expressed in neonatal muscle. MIR-544’s role as an oncogene is established in gastric cancer. It promotes invasion of lung cancer cells by targeting CDH1 and upregulation of VIM. MiR-544a induces EMT by activation of WNT signaling in gastric cancer and immune escape in hepatoma cells. Reduction of CDH1 and upregulation of VIM, SNAI1, and ZEB1 by miR-544a induces EMT (109). MiR-544a directly targets CDH1 and AXIN2 leading to nuclear translocation and stabilization of CTNNB1. These data collectively suggest that the expression of ZEB is regulated by miRNA cluster and that ZEB along with other EMT-TFs induces EMT and metastasis in multiple cancer. Thus, targeting the ZEB-miRNA cluster axis could be used for the management of cancer.

Taken together, a wide array of transcription factors is associated and required to drive the multistep EMT program and are being regulated by a variety of EMT-TFs and signaling pathways. The EMT-TFs acting exclusively or synergistically, and target common pathways to induce EMT. MiRNA clusters reported to regulate multiple signaling pathways associated with EMT are discussed below.

Receptor tyrosine kinases (RTKs) are high-affinity transmembrane receptors which bind to growth factors, cytokines, and hormones. RTKs play an important role in growth, proliferation differentiation and movement of cells (122). RTKs, inappropriately regulated, and expressed in many cancer types, are strongly implicated in EMT (15). Binding of growth factors (EGF, FGF, IGF, HGF, CFC) to RTKs leads to activation of EMT-TFs such as SNAIL, SLUG, ZEB and TWIST via multiple signaling axis notably PI3K-AKT-glycogen synthase kinase 3 beta (GSK3β)-β-catenin axis or RAS-MAPK signaling (15).

The miRNA cluster can either activate or inhibit the expression of tyrosine kinase pathway genes (123). For example, miRNA cluster 23a/24-2 regulates EGFR and c-MET expression in lung cancer. Cancer cell invasion and metastasis are driven by c-MYC induced miR-23a/27a cluster (124). The treatment of NSCLC cells by TGF-β1 activates miR-134/miR-487b/miR-655 cluster. MiR-134/miR-487b/miR-655 by targeting membrane-associated guanylate kinase (MAGI2) induces gefitinib resistance (42). In chronic myelogenous leukemia (CML) both miR-17/92 cluster and tyrosine kinase activity were reported (125). Overexpression of receptor tyrosine kinases and miR-221/222 is reported in breast cancer. MET, EGF, and miR-3a/24-2 interaction are reported in non-small cell lung cancer (124). MiR-143/145 cluster is downregulated in KRAS mutant pancreatic cancer cells. Further, forced expression of this miRNA cluster inhibited tumorigenesis (126). Interestingly, the miR-143/145 cluster also targets KRAS and RREB1 and is an inhibitor of Ras signaling (127). MiRNA clusters can promote EMT by targeting and inhibiting negative regulators of PI3K-AKT signaling. For example, miR-106b/25 (128), miR-23a/24-2 (129) and miR-17/106 (130) activate PI3K- AKT signaling by downregulation of PTEN. MiR-27a belonging to miR-23a/24-2 synergizes with AKT by targeting FOXO1 (131). MiR-15/16 is a tumor suppressive cluster that inhibits prostate cancer cell invasion by suppressing the TGF-β signaling pathway (132). TGF-β and FGF-2 are reported to promote EMT in lung adenocarcinoma (PC-9 and HCC-827) cells through Smad3, MEK/extracellular-signal-regulated kinase (ERK), and mTOR pathways. Overexpression of miR-16 reduces the expression of fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 2 (VEGFR2) in endothelial cells (133). MiR-143/145 is repressed by the activation of EGFR and Ras signaling (114). The miR-143 expression has been negatively correlated with EGFR in NSCLC cells. Transfection studies have shown that EGFR is a target of miR-143. MiR-99a/let-7/miR-125b is downregulated in malignant pleural mesothelioma (134, 135). MiRNA-99a targets (insulin-like growth factor 1 receptor) IGF1R/PI3K/AKT/mTOR and inhibits proliferation, migration, and invasion of cancer cells (136). Thus, altered expression of miRNAs can lead to inappropriate activation of tyrosine kinase pathways contributing to aggressiveness, progression and tumor resistant phenotypes in cancer cells via activation of EMT.

ILKs belong to Raf-like kinases (RAF) subfamily and are an intracellular serine/threonine kinase. It consisting of 5 ankyrin repeats, a phosphoinositide binding motif, and a kinase catalytic domain. ILKs act as a regulator of development and tissue homeostasis (137, 138). Being a downstream mediator of the Smad-TGF-β1 signaling pathway, the ILK pathway is implicated in EMT and the acquisition of invasive and metastatic phenotypes (138). ILKs interact with integrins and can be stimulated by growth factors and chemokines in a PI3K dependent manner. Overexpression of ILKs is reported in multiple cancers and inhibition of their activities could be used as a potential mechanism to control invasion and metastasis in cancer (139). ILKs are required for integrin-dependent focal adhesion. ILKs promote EMT via AKT1/GSK3β/CTNNB1 axis. Forced expression of ILK increased invasion and migration of cancer cells through nuclear translocation of CTNNB1 and downregulation of CDH1 (140). MiR-424/503 cluster expression is downregulated in SRC-transformed cells with its forced expression inhibiting cancer cell invasion (141). MiR-23b and miR-27b belonging to miR-23b/24-1 have also been downregulated during cSrc-induced transformed cells (142). MiRNAs have been reported to regulate the expression of specific integrins. The miR-17/92 cluster consists of 6 miRNA encoding genes namely miR-17, miR-18a, miR-19a, miR-19b, miR-20a and miR-92a (143). MiR-92a is reported to suppress integrin α5 expression (144). In renal cell cancers, integrin α5 promotes metastasis (145). In ovarian cancer, the silencing of ILK upregulates miR-15a-miR-16-1 cluster (113). Integrin-α6β4 is a receptor for laminin binding which promotes motility of cells in various types of cancer. In breast cancer, Integrin-α6β4 downregulates the expression of miR-25/32/92abc/363/363-3p/ 367 and miR-99ab/100 (146).

Ras is a small GTP-binding protein that controls proliferation, differentiation, adhesion, apoptosis, and migration of cells in normal and pathological conditions (147). Overexpression of Ras signaling promotes growth, proliferation, migration, and invasion of cancer cells. Ras overexpression induces actin cytoskeleton remodeling, inhibits apoptosis and confers resistance to anticancer agents (147). Ras signaling induced EMT involves activation of MAPK, Hypoxia-Inducible Factor 1-Alpha (HIF1α) and PI3K/AKT/mTOR pathways, induction of SANIL2, TWIST1/2, ZEB1, and inhibition of CDH1 (148). Activation of the RAS pathway is reported to regulate the expression of many miRNA clusters and vice versa (149). Ras initiates tumor-promoting pathways by repression of the miR-143/145 cluster (126). MiR-379/miR-656 is a downregulated miRNA cluster in glioblastoma (GBM) (127). Lassad et al 2015, showed an inverse correlation between expression of CYLD lysine 63 deubiquitinase (CYLD) and KRAS with the miR-183-96-182 cluster (150). The upregulation of AKT signaling is reported to induce EMT. MiR-154 and miR-37, belonging to DLK1-DIO3 microRNA mega-cluster, is elevated in prostate cancer, and it results in activation of E2F signaling, Ras pathway, hypoxia-inducible factor signaling, and the WNT and TGF-β pathways (151). MiR-144/451 inhibits esophageal cancer cell migration by downregulation of ERK/c-Myc signaling (152). Many previous studies have established the role of the Ras–MEK–ERK signaling pathway in EMT. The miR182 activates Ras–MEK–ERK signaling by suppressing RAS p21 protein activator 1 (RASA1) and sprouty-related EVH1 domain containing 1 (SPRED1) expression in squamous cell carcinoma of the oral cavity (153). KRAS overexpression induces NF-kB and inhibits CDH1 expression via SNAIL and MMP9 (154, 155). Ras-Raf-MEK1/2-ERK activates SLUG and represses CDH1 expression (156). Ras-Ral-RAC family small GTPase (Rac), P21 activated kinases (PAK), Myosin light chain phosphatase (MLCP), Megalencephalic Leukoencephalopathy with Subcortical Cysts 1 (MLC) axis are implicated in focal adhesion formation contributing to EMT (157). MiR-23/24/27 cluster is downregulated in keratinocytes having HRas protooncogene (HrasG12 V) (158). MiR-17-92 regulation of Ras signaling is also reported (159). MiR-411 is a member of 4q32.31 miRNA cluster which promotes growth, proliferation, and metastasis in non-small-cell lung carcinoma (NSCLC) cell (160). miR-411-5p targets growth factor receptor bound protein 2 (GRB2)-son of sevenless homolog (SOS)-Ras signaling to prevent migration and invasion of breast cancer cells (161). Activation of the miR-221/222 cluster by Ras signaling is reported in basal-like breast cancer cells resulting in induction of EMT by downregulation Transcriptional Repressor GATA Binding 1 (TRPS1), a repressor of ZEB2 (115, 116).

Notch signaling is one of the highly conserved signaling pathways important for a cell to cell communication, cell differentiation, proliferation, invasion, migration, and apoptosis. Activation of Notch is reported to drive aberrant expression of EMT-TFs such as TWIST, SNAIL, SLUG, and ZEB1/2, with concomitant downregulation of CDH1 (162). Notch signaling activates genes associated with differentiation, survival, migration, invasion such as CCND1, c-Myc, and others. Notch crosstalk with EMT-TFs (SNAIL, SLUG) and growth factors (TGF-β, FGF, and PDGF) is implicated in EMT, chemoresistance, and metastasis (162). Overexpression of miR-200b inhibits Notch-1 expression (163, 164). Direct repression of the Delta/Notch pathway by miR-449 cluster controls vertebrate multiciliogenesis (165). Notch signaling can also activate oncogenic miRNA clusters. For instance, the activation of miR-17/92 in cancer by the Notch pathway leads to cellular proliferation. MiR-17/92 cluster promoter is predicted to poses a binding site for Hes family transcription factor 1 (HES1), an effector of Notch signaling. Moreover, B-Raf proto-oncogene (BRAFV600E) induces the expression of miR-17-92 via activation of Notch signaling (166). MiRNA-134 is a member of the delta-like non-canonical notch ligand - iodothyronine deiodinase (DLK1-DIO3) cluster. MiRNA-134 is reported to regulate the expression of protein O-glucosyltransferase 1 (POGLUT1) and Notch pathway proteins in human endometrial cancers (167). Members of miR-206/miR-133b are reported to target NOTCH 3 in HeLa cells (168, 169).

Activation of the canonical Wnt pathway, non-canonical planar cell polarity pathway, and non-canonical Wnt/calcium pathway is reported in various cancers. Many members of WNT signaling (WNTs, CTNNB1) either directly or indirectly activates SNAIL, SLUG, ZEB1/2, TWISTs, inhibit CDH1, and participate in the induction of EMT program (15, 170). MiRNA clusters are important for precise regulation of WNT signaling. Aberrant expression of miRNA clusters is reported to activate WNT signaling and to contribute to EMT. For example, transactivation of miR-371-373 by CTNNB1/ lymphoid enhancer binding factor 1 (LEF1) modulates Wnt/β-catenin-signaling pathways (171). MiR-30a/b/c/d/e-5p interaction with members of the canonical WNT pathway is reported to affect the treatment outcome in multiple myeloma (172). Crosstalk between PTEN/PI3K and Wnt pathway plays an important role in the subcellular localization of CTNNB1. Activation of the Wnt/β-catenin pathway and loss of PTEN activity is important for the initiation and progression of endometrial cancer (173). MiR-17/92 cluster by targeting PTEN/PI3K pathway promotes chemotherapeutic resistance and metastasis (174, 175). Metastasis suppressor protein 1 (MTSS1) is regulated by PTEN and is reported to inhibit EMT via inactivation of PI3K/AKT signaling (176). MiR-200a is an inhibitor of CTNNB1. MiR-145 is a tumor-suppressive miRNA belonging to the miR-143/miR-145 cluster. It targets catenin δ-1, disturbs the nuclear translocation of CTNNB1, and inhibits the transcription of c-Myc and CCND1 (177).

This pathway plays an important role in embryonic development, adult tissue maintenance, renewal, regeneration, differentiation, polarity, and proliferation. The defect in the hedgehog signaling pathway is reported in some cancers, especially during metastasis (178). It is a crucial regulator of EMT and is responsible for chemoresistance properties of human pancreatic Panc-1 cancer stem cells (179). Hedgehog (Hh) signaling participates in metastatic cascade by induction of EMT and angiogenesis (180). Hh signaling contributes to tumor development by inducing the expression of pro-tumorigenic genes such as CCND1, ABCG2, BCL2, SNAIL, WNT2, VEGF and TGF-β (181). In liver cancer, hedgehog enhances the expression of FAK/AKT, leading to increased secretion of MMP2 and MMP9 inducing EMT (182). Hedgehog via patched (PTCH) and glioma-associated oncogene (GLI) is reported to induce SNAIL expression and EMT (183). Human medulloblastoma shows constitutive activation of Sonic Hedgehog signaling and overexpression miR-17/92 cluster (184, 185). MiR-193b/365a cluster is downregulated in cutaneous squamous cell carcinomas (186). Hedgehog signaling activates its downstream target genes such as BCL2, FOXC2, Jagged 2 (JAG2), and MYCN via Smoothened (SMO) and GLI (187). MiR-193b is a transcriptional repressor of SMO. In colorectal cancer, hedgehog promotes EMT by activation of MMP2 and MMP9 via the induction of FAK and AKT. MiR-125b belonging to miR-99a/let-7c/miR-125b cluster expression is significantly low in ovarian, oral, cholangiocarcinoma and prostate cancer (188–191). MiR-125b has been reported to inhibit EMT by targeting hedgehog (192).