miR‐137 targets Cdc42 expression, induces cell cycle G1 arrest and inhibits invasion in colorectal cancer cells

Abstract

miRNAs have emerged as post-transcriptional regulators that are critically involved in the pathogenesis of a number of human cancers. Cdc42, one of the best characterized members of the Rho GTPase family, is found to be up-regulated in several types of human tumors and has been implicated in cancer initiation and progression. In the present study, we have identified miR-137 as a potential regulator of Cdc42 expression. A bioinformatics search revealed a putative target-site for miR-137 within the Cdc42 3 0 UTR at nt 792-798, which is highly conserved across different species. Expression of miR-137 in colorectal cancer cell lines was found inversely correlated with Cdc42 expression. miR-137 could significantly suppress Cdc42 3 0 UTR luciferase-reporter activity, and this effect was not detectable when the putative 3 0 UTR target-site was mutated. Consistent with the results of the reporter assay, ectopic expression of miR-137 reduced both mRNA and protein expression levels of Cdc42 and mimicked the effect of Cdc42 knockdown in inhibiting proliferation, inducing G1 cell cycle arrest, and blocking invasion of the colorectal cancer cells, whereas anti-miR-137 expression led to the opposite effect. Furthermore, expression of miR-137 suppressed the immediate downstream effector of Cdc42, PAK signaling. Our results suggest that miR-137 may have a tumor suppressor function by directly targeting Cdc42 to inhibit the proliferation and invasion activities of colorectal cancer cells. They raise an interesting possibility that Cdc42 activity and function can be controlled by miRNAs in addition to the classic regulators such as guanine nucleotide exchange factors and GTPase-activating proteins.

Expression analysis of Cdc42 in lung cancer and modulation of its expression by curcumin in lung cancer cell lines

“…In contrast, downregulation of Cdc42 signals can inhibit anchorage-independent growth and induce apoptosis via the PI(3)K-Akt and Erk signaling cascades and the p53 tumor suppressor (8). Consistent with these reports, Cdc42 silencing by small hairpin RNA was able to reverse the metastatic and growth behavior of human colorectal cancer cells and bladder cancer cells (9,10). Taken together, the observed effects of Cdc42 over-expression and silencing on the cell malignant transformation indicate a role for Cdc42 in regulating tumor metastasis and progression.…”

MicroRNA signatures differentiate melanoma subtypes

“…[19][20][21][22][23][24] We therefore evaluated the expression levels of seven targets of miR-137 (MITF, MIB1, CDK6, CDC42, JARID1B, EZH2 and E2F6 ) and one upstream regulator of miR-137 (MECP2) employing the NimbleGen whole-genome expression array 25 in a subset of the WT and MUT samples (n = 19 and 5, respectively). Two transcript variants were spotted on the array for MECP2 (NM_004992 and NM_001110792) and CDK6 (NM_001259 and NM_001145306).…”

miR-137 Regulates the Tumorigenicity of Colon Cancer Stem Cells through the Inhibition of DCLK1

“…Actually, some reports have shown that miR-137 has various targets, such as Cdc42, pyruvate kinase isozymes, Formin-like 2, and paxillin, which are related to invasion, the inhibition of the Warburg effect, and metastasis in colorectal cancers, respectively (31)(32)(33)(34). In addition, miR-137 is epigenetically regulated through promoter hypermethylation in colorectal cancers and the epigenetic silencing of miR-137 occurs at the early stage of colorectal carcinogenesis (35).…”