miR-137 targets Cdc42 expression, induces cell cycle G1 arrest and inhibits invasion in colorectal cancer cells.
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' 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' UTR luciferase-reporter activity, and this effect was not detectable when the putative 3' 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.
Liu
Ming
M
Laboratory of Signal Transduction & Molecular Targeted Therapy, State Key Laboratory of Biotherapy/Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China.
Lang
Nan
N
Qiu
Meng
M
Xu
Feng
F
Li
Qiu
Q
Tang
Qiulin
Q
Chen
Ji
J
Chen
Xi
X
Zhang
Siyuan
S
Liu
Zhen
Z
Zhou
Jitao
J
Zhu
Yajie
Y
Deng
Yu
Y
Zheng
Yi
Y
Bi
Feng
F
D020413:3' Untranslated Regions; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003094:Collagen / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D004338:Drug Combinations; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000502:physiology*; D011509:Proteoglycans / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D020413:3' Untranslated Regions; D004338:Drug Combinations; D007797:Laminin; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D011509:Proteoglycans; D012333:RNA, Messenger; C059485:matrigel; D003094:Collagen; D008156:Luciferases; D020764:cdc42 GTP-Binding Protein