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A Link between mir-100 and FRAP1/mTOR in Clear Cell Ovarian Cancer

Departments of Pathology (A.K.N., Z.Y., P.H.G., M.L.A., M.M.M.), Molecular and Human Genetics (A.K.N., M.M.M.), Medicine (C.J.C.), Obstetrics and Gynecology (E.O., S.M.H., M.L.A.), Molecular and Cellular Biology (M.M.M.), the Dan L. Duncan Cancer Center (C.J.C., P.H.G., S.M.H., M.L.A., M.M.M.), and the Human Genome Sequencing Center (P.H.G., J.G.R.), Baylor College of Medicine, Houston, Texas 77030; Departments of Physics (H.Z.), Biology and Biochemistry (P.H.G.), and Chemistry (J.G.R.), University of Houston, Houston, Texas 77004; Department of Obstetrics and Gynecology (H.I.), Tottori University School of Medicine, Yonago 683-8504, Japan; and Breast Cancer Translational Research Laboratory (N.T.U.), Departments of Stem Cell Transplantation and Cellular Therapy (N.T.U.) and Breast Medical Oncology (N.T.U.), University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., The Stuart A. Wallace Chair and Professor, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: mmatzuk{at}bcm.edu; or Matthew L. Anderson, M.D., Ph.D., Department of Obstetrics and Gynecology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: matthew{at}bcm.edu.

MicroRNAs (miRNAs) are small noncoding RNAs that direct gene regulation through translational repression and degradation of complementary mRNA. Although miRNAs have been implicated as oncogenes and tumor suppressors in a variety of human cancers, functional roles for individual miRNAs have not been described in clear cell ovarian carcinoma, an aggressive and chemoresistant subtype of ovarian cancer. We performed deep sequencing to comprehensively profile miRNA expression in 10 human clear cell ovarian cancer cell lines compared with normal ovarian surface epithelial cultures and discovered 54 miRNAs that were aberrantly expressed. Because of the critical roles of the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1/mammalian target of rapamycin (mTOR) pathway in clear cell ovarian cancer, we focused on mir-100, a putative tumor suppressor that was the most down-regulated miRNA in our cancer cell lines, and its up-regulated target, FRAP1/mTOR. Overexpression of mir-100 inhibited mTOR signaling and enhanced sensitivity to the rapamycin analog RAD001 (everolimus), confirming the key relationship between mir-100 and the mTOR pathway. Furthermore, overexpression of the putative tumor suppressor mir-22 repressed the EVI1 oncogene, which is known to suppress apoptosis by stimulating phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog 1 signaling. In addition to these specific effects, reversing the expression of mir-22 and the putative oncogene mir-182 had widespread effects on target and nontarget gene populations that ultimately caused a global shift in the cancer gene signature toward a more normal state. Our experiments have revealed strong candidate miRNAs and their target genes that may contribute to the pathogenesis of clear cell ovarian cancer, thereby highlighting alternative therapeutic strategies for the treatment of this deadly cancer.