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MicroRNA Microarray Identifies Let-7i as a Novel Biomarker and Therapeutic Target in Human Epithelial Ovarian Cancer

¹ Center for Research on Early Detection and Cure of Ovarian Cancer, ² Abramson Cancer Center, ³ Department of Obstetrics and Gynecology, ⁴ The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania; ⁵ Departments of Obstetrics and Gynecology, and Pathology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland; ⁶ Departments of Molecular Virology, Immunology, and Medical Genetics, Ohio State University, Columbus, Ohio; ⁷ Department of Medical Micorobiology and Immunology, Creighton University, Omaha, Nebraska; ⁸ Experimental Therapeutics and Cancer Genetics, University of Texas, M. D. Anderson Cancer Center, Houston, Texas; and ⁹ Department of Obstetrics and Gynecology, University of Turin, Turin, Italy

Requests for reprints: Lin Zhang, Room 1209 BRB II/III, 421 Curie Boulevard, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Phone: 215-573-4780; Fax: 215-573-7627; E-mail: linzhang{at}mail.med.upenn.edu.

Key Words: let-7i • microRNA • ovarian cancer • chemotherapy

MicroRNAs (miRNA) are approximately 22-nucleotide noncoding RNAs that negatively regulate protein-coding gene expression in a sequence-specific manner via translational inhibition or mRNA degradation. Our recent studies showed that miRNAs exhibit genomic alterations at a high frequency and their expression is remarkably deregulated in ovarian cancer, strongly suggesting that miRNAs are involved in the initiation and progression of this disease. In the present study, we performed miRNA microarray to identify the miRNAs associated with chemotherapy response in ovarian cancer and found that let-7i expression was significantly reduced in chemotherapy-resistant patients (n = 69, P = 0.003). This result was further validated by stem-loop real-time reverse transcription-PCR (n = 62, P = 0.015). Both loss-of-function (by synthetic let-7i inhibitor) and gain-of-function (by retroviral overexpression of let-7i) studies showed that reduced let-7i expression significantly increased the resistance of ovarian and breast cancer cells to the chemotherapy drug, cis-platinum. Finally, using miRNA microarray, we found that decreased let-7i expression was significantly associated with the shorter progression-free survival of patients with late-stage ovarian cancer (n = 72, P = 0.042). This finding was further validated in the same sample set by stem-loop real-time reverse transcription-PCR (n = 62, P = 0.001) and in an independent sample set by in situ hybridization (n = 53, P = 0.049). Taken together, our results strongly suggest that let-7i might be used as a therapeutic target to modulate platinum-based chemotherapy and as a biomarker to predict chemotherapy response and survival in patients with ovarian cancer. [Cancer Res 2008;68(24):10307–14]

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