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MiR-15a and MiR-16 Control Bmi-1 Expression in Ovarian Cancer

Departments of ¹ Biochemistry and Molecular Biology and ² Biomedical Engineering, College of Medicine, Mayo Clinic, Rochester, Minnesota; and ³ Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Resham Bhattacharya, Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, MN-55905. Phone: 507-538-0563; Fax: 507-284-1767; E-mail: bhattacharya.resham{at}mayo.edu.

Oncogenic activation of Bmi-1 is found in a wide variety of epithelial malignancies including ovarian cancer, yet a specific mechanism for overexpression of Bmi-1 has not been determined. Thus, realizing the immense pathologic significance of Bmi-1 in cancer, we wanted to investigate if microRNA (miRNA) aberrations played a role in the regulation of Bmi-1 in ovarian cancer. In this report, we identify two miRNAs, miR-15a and miR-16, that are underexpressed in ovarian cell lines and in primary ovarian tissues. We show that these miRNAs directly target the Bmi-1 3' untranslated region and significantly correlate with Bmi-1 protein levels in ovarian cancer patients and cell lines. Furthermore, Bmi-1 protein levels are downregulated in response to miR-15a or miR-16 expression and lead to significant reduction in ovarian cancer cell proliferation and clonal growth. These findings suggest the development of therapeutic strategies by restoring miR-15a and miR-16 expression in ovarian cancer and in other cancers that involve upregulation of Bmi-1. [Cancer Res 2009;69(23):OF1–6]

Key Words: MicroRNA • ovarian cancer • Bmi-1 • clonal growth • proliferation