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

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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

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Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Chao, A., Lin, C. Y., Lee, Y. S., Tsai, C. L., Wei, P. C., Hsueh, S., Wu, T. I., Tsai, C. N., Wang, C. J., Chao, A. S., Wang, T. H., & Lai, C. H. (2012). Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2. Oncogene, 31(6), 764-775. https://doi.org/10.1038/onc.2011.269