title: Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2.
abstract: MicroRNAs (miRNAs) play important roles in tumorigenesis by regulating oncogenes and tumor-suppressor genes. In this study, miR-187 and miR-200a were found to be expressed at higher levels in ovarian cancers than in benign tumors. In patients with ovarian cancer, however, higher levels of miR-187 and miR-200a expression were paradoxically associated with better OS and recurrence-free survival. Further, multivariate analysis showed that miR-187 served as an independent prognostic factor for patients with ovarian cancer (n=176). Computational prediction and microarray results indicated that miR-187 directly targeted Disabled homolog-2 (Dab2), and luciferase reporter assays confirmed that the target site of miR-187 was located at the 3'-UTR of the Dab2 gene. Generally considered as a tumor-suppressor gene, Dab2 may actually promote tumor progression in advanced cancers through epithelial-to-mesenchymal transition (EMT). Ectopic expression of miR-187 in cancer cells promoted cell proliferation, but continued overexpression of miR-187 suppressed Dab2 and inhibited migration. Suppression of miR-187 upregulated Dab2, which, by inhibiting E-cadherin levels while stimulating vimentin and phospho-FAK levels, promoted EMT. Reduced ovarian cancer Dab2 histoscores correlated with high miR-187 levels and improved outcomes of patients. Collectively, these results demonstrate distinct dual roles of Dab2 in cell proliferation and tumor progression. In the initial steps of tumorigenesis, upregulated miR-187 suppresses Dab2, promoting cell proliferation. During the later stages, however, continued increased levels of miR-187 inhibits the Dab2-dependent EMT that is associated with tumor invasiveness, which is presumed to be the reason why cancers with high miR-187 levels were associated with better survivals.
authors: Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Tao-Yuan, Taiwan.
authors: A
authors: A
authors: Chao
authors: C-Y
authors: CY
authors: Lin
authors: Y-S
authors: YS
authors: Lee
authors: C-L
authors: CL
authors: Tsai
authors: P-C
authors: PC
authors: Wei
authors: S
authors: S
authors: Hsueh
authors: T-I
authors: TI
authors: Wu
authors: C-N
authors: CN
authors: Tsai
authors: C-J
authors: CJ
authors: Wang
authors: A-S
authors: AS
authors: Chao
authors: T-H
authors: TH
authors: Wang
authors: C-H
authors: CH
authors: Lai
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D016372:RNA, Antisense / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D013997:Time Factors; D025521:Tumor Suppressor Proteins
chemical_list: D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; C102885:DAB2 protein, human; C571843:MIRN187 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D016372:RNA, Antisense; D025521:Tumor Suppressor Proteins