title: miR-133 is a key negative regulator of CDC42-PAK pathway in gastric cancer.
abstract: Cell division cycle 42 (CDC42), an important member of the Ras homolog (Rho) family, plays a key role in regulating multiple cellular processes such as cell cycle progression, migration, cell cytoskeleton organization, cell fate determination and differentiation. Among the downstream effectors of CDC42, P21-activated kinases (PAKs) obtain the most attention. Although a large body of evidence indicates that CDC42/PAKs pathway plays important role in tumor growth, invasion and metastasis, the mechanism of their negative regulation remains unclear. Here, we identified CDC42, a PAKs activating factor, was a target of miR-133. Ectopic overexpression of miRNAs not only downregulated CDC42 expression and PAKs activation, but also inhibited cancer cell proliferation and migration. We also found that miR-133 was down-regulated in 180 pairs gastric cancer tissues. miR-133 expression was negatively associated with tumor size, invasion depth and peripheral organ metastasis. Besides, dysfunction of miR-133 was an independent prognosis factor for overall survival. Our findings could provide new insights into the molecular mechanisms of gastric carcinogenesis, and may help facilitating development of CDC42/PAK-based therapies for human cancer.
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China.
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Cheng
authors.affiliation: Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang 110001, China.
authors.forename: Funan
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China.
authors.forename: Guanqiao
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China.
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China. Electronic address: fli@mail.cmu.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics*; D020764:cdc42 GTP-Binding Protein / Q000235:genetics*; D054462:p21-Activated Kinases / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein
keywords: Activation; CDC42; Gastric cancer; Invasion; miR-133; p21-activated kinase