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

Oncogene volume 31, pages 764–775 (2012)Cite this article

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.

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Acknowledgements

We thank Ching-Ling Wang, Jung-Erh Yang and Ying-Yu Lin for technical assistance; the Division of Gynecologic Oncology of Chang Gung Memorial Hospital for clinical data retrieval; Shih-Yee Mimi Wang (University of Illinois College of Medicine, Rockford) for language editing and Professor Ching-Ping Tseng (Chang Gung University) for discussion and advices. This study was supported by grants from the National Science Council (NSC99-2314-B-182A-087-MY3 to AC), the National Research Program for Genomic Medicine (NSC97-3112-B-001-020 to Y-SL), the Chang Gung Medical Foundation (CMRPG360953/4, 391451 to AC; IRB No. 95-1364B, 97-1444C, 99-2072C, 99-2411C) and the Department of Health (DOH99-TD-B-111-005 to C-HL; DOH99-TD-C-111-006 to AC and T-HW).

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  1. A Chao and C-Y Lin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Tao-Yuan, Taiwan

    A Chao, C-Y Lin, C-L Tsai, P-C Wei, T-I Wu, C-J Wang, A-S Chao, T-H Wang & C-H Lai

  2. Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital, Gwei-Shan, Taiwan

    Y-S Lee & T-H Wang

  3. Department of Biotechnology, Ming-Chuan University, Tao-Yuan, Taiwan

    Y-S Lee

  4. Graduate Institute of Biomedical Sciences, Chang Gung University, Gwei-Shan, Taiwan

    P-C Wei & T-H Wang

  5. Department of Clinical Pathology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Tao-Yuan, Taiwan

    S Hsueh

  6. Graduate Institute of Clinical Medical Sciences, Chang Gung University, Gwei-Shan, Taiwan

    C-N Tsai

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Chao, A., Lin, CY., Lee, YS. et al. Regulation of ovarian cancer progression by microRNA-187 through targeting Disabled homolog-2. Oncogene 31, 764–775 (2012). https://doi.org/10.1038/onc.2011.269

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