Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2

A. Chao, C. Y. Lin, Y. S. Lee, C. L. Tsai, P. C. Wei, S. Hsueh, T. I. Wu, C. N. Tsai, C. J. Wang, A. S. Chao, T. H. Wang, C. H. Lai

Research output: Contribution to journalArticlepeer-review

109 Citations (Scopus)

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 (n176). 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.

Original languageEnglish
Pages (from-to)764-775
Number of pages12
JournalOncogene
Volume31
Issue number6
DOIs
Publication statusPublished - Feb 2012
Externally publishedYes

Keywords

  • Dab2
  • epithelial-mesenchymal transition (EMT)
  • microRNA
  • miR-187

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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