title: miR-200b induces cell cycle arrest and represses cell growth in esophageal squamous cell carcinoma.
abstract: miR-200b is a pleiotropically acting microRNA in cancer progression, representing an attractive therapeutic target. We previously identified miR-200b as an invasiveness repressor in esophageal squamous cell carcinoma (ESCC), whereas further understanding is warranted to establish it as a therapeutic target. Here, we show that miR-200b mitigates ESCC cell growth by inducing G2-phase cell cycle arrest and apoptosis. The expression/activation of multiple key cell cycle regulators such as CDK1, CDK2, CDK4 and Cyclin B, and the Wnt/β-Catenin signaling are modulated by miR-200b. We identified CDK2 and PAF (PCNA-associated factor), two important tumor-promoting factors, as direct miR-200b targets in ESCC. Correlating with the frequent loss of miR-200b in ESCC, both CDK2 and PAF levels are significantly increased in ESCC tumors compared to case-matched normal tissues (n = 119, both P < 0.0001), and correlate with markedly reduced survival (P = 0.007 and P = 0.041, respectively). Furthermore, CDK2 and PAF are also associated with poor prognosis in certain subtypes of breast cancer (n = 1802) and gastric cancer (n = 233). Although CDK2 could not significantly mediate the biological function of miR-200b, PAF siRNA knockdown phenocopied while restored expression of PAF abrogated the biological effects of miR-200b on ESCC cells. Moreover, PAF was revealed to mediate the inhibitory effects of miR-200b on Wnt/β-Catenin signaling. Collectively, the pleiotropic effects of miR-200b in ESCC highlight its potential for therapeutic intervention in this aggressive disease.
authors: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong 515041, China.|Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.|Department of Molecular Oncology, British Columbia Cancer Research Centre and Department of Pathology, University of British Columbia, Vancouver, British Columbia V5Z 1L3, Canada and.
authors: Hai-Feng
authors: HF
authors: Zhang
authors: Department of Laboratory Medicine and Pathology , University of Alberta , Edmonton , Alberta T6G 2E1 , Canada.
authors: Abdulraheem
authors: A
authors: Alshareef
authors: Department of Laboratory Medicine and Pathology , University of Alberta , Edmonton , Alberta T6G 2E1 , Canada.
authors: Chengsheng
authors: C
authors: Wu
authors: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, Guangdong 515041, China.|Institute of Oncologic Pathology, Shantou University Medical College, Shantou, Guangdong 515041, China.
authors: Ji-Wei
authors: JW
authors: Jiao
authors: Department of Molecular Oncology, British Columbia Cancer Research Centre and Department of Pathology, University of British Columbia, Vancouver, British Columbia V5Z 1L3, Canada and.
authors: Poul H
authors: PH
authors: Sorensen
authors: Department of Laboratory Medicine and Pathology , University of Alberta , Edmonton , Alberta T6G 2E1 , Canada.
authors: Raymond
authors: R
authors: Lai
authors: Institute of Oncologic Pathology , Shantou University Medical College , Shantou , Guangdong 515041 , China.
authors: Li-Yan
authors: LY
authors: Xu
authors: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area , Shantou University Medical College , Shantou , Guangdong 515041 , China.
authors: En-Min
authors: EM
authors: Li
mesh_terms: D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D059565:G2 Phase Cell Cycle Checkpoints; D016147:Genes, Tumor Suppressor; D006801:Humans; D035683:MicroRNAs / Q000502:physiology*; D011379:Prognosis; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000502:physiology
chemical_list: C495270:CTNNB1 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C425208:PCLAF protein, human; D051176:beta Catenin; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2