Cell Cycle and Senescence miR-106a Represses the Rb Tumor Suppressor p130 to Regulate Cellular Proliferation and Differentiation in High-Grade Serous Ovarian Carcinoma

The degree of differentiation in human cancers generally reflects the degree of malignancy, with the most undifferentiated cancer being also the highest grade and the most aggressive. High-grade serous ovarian carcinomas (HGSOC) are poorly differentiated and fast-growing malignancies. The molecular mechanisms underlying the poor differentiation of HGSOC has not been completely characterized. Evidence suggests that miRNA, miR are dysregulated in HGSOC. Therefore, we focused on those miRNAs that are relevant to tumor differentiation. Expression profiling of miRNAs in HGSOC, indicated miR-106a and its family members were significantly upregulated. Upregulation of miR-106a was further validated by real-time reverse transcriptase PCR (qRT-PCR) and miRNA in situ hybridization in a large cohort of HGSOC specimens. Overexpression of miR-106a in benign and malignant ovarian cells significantly increased the cellular proliferation rate and expanded the side-population fraction. In particular, SKOV3 cells with miR-106a overexpression had significantly higher tumor initial/stem cell population (CD24and CD133-positive cells) than control SKOV3 cells. Among many miR-106a predicated target genes, p130 (RBL2), an retinoblastoma (Rb) tumor suppressor family member, was not only confirmed as a specific target of miR-106a but also related to tumor growth and differentiation. The importance of mir-106a and RBL2 was further demonstrated in vivo, in which, SKOV3 cells overexpressing miR-106a formed poorly differentiated carcinomas and had reduced RBL2 levels. To our knowledge, this is the first study of miR-106a mediating proliferation and tumor differentiation in HGSOC. Implications:The current study suggests that the RB tumor suppressor pathway is a critical regulator of growth and differentiation in HGSOC. Mol Cancer Res; 11(11); 1314–25. 2013 AACR. Introduction Ovarian cancer is a deadly disease. According to the American Cancer Society, approximately 21,000 women developed ovarian cancer and approximately 15,000 women died from this disease in the United States in 2011. Despite great efforts in clinical and medical research, the overall survival rate of ovarian cancer has not changed in the past 50 years (1). Histologic and molecular heterogeneity has complicated our understanding of the tumor biology and its behavior and has limited the treatment options for this deadly disease. For example, high-grade serous ovarian carcinomas (HGSOC), accounting for up to 60% of ovarian epithelial carcinoma, are genetically and histologically heterogeneous tumors. According to The Cancer Genomic Atlas (TCGA), HGSOC can be further divided into four subtypes defined as Differentiated, Immunoreactive, Mesenchymal, and Proliferative based on the different molecular signatures from global gene and miRNA profiles (2). The degree of differentiation of human cancers is used to score the degree of malignancy, with the most undifferentiated cancer being the highest grade and most aggressive. Although the exact mechanisms in controlling HGSOC differentiation are probably complex and remain to be fully characterized, the TCGA study indicates that a subset of gene and miRNA are associated with tumor differentiation (2). miRNAs are a group of small noncoding RNAs that are significantly dysregulated in ovarian epithelial carcinoma (3). Furthermore, the miRNA signature can be used for tumor classification and for grading differentiation (4). In addition to the findings of altered miRNA expression in association Authors' Affiliations: Institute of Cell Biology, Ministry of Education Key Laboratory of Experimental Teratology and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine; Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong, China; Department of Pathology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University School of Medicine, Chicago, Illinois; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Department of Pathology, New York University, New York, New York Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Corresponding Author: Jian-Jun Wei, Department of Pathology, Northwestern University School of Medicine, Feinberg 7-334, 251 East Huron Street, Chicago, IL 60611. Phone: 312-926-1815; Fax: 312-926-3127; E-mail: [email protected] doi: 10.1158/1541-7786.MCR-13-0131 2013 American Association for Cancer Research. Molecular Cancer Research Mol Cancer Res; 11(11) November 2013 1314 on June 16, 2017. © 2013 American Association for Cancer Research. mcr.aacrjournals.org Downloaded from Published OnlineFirst September 17, 2013; DOI: 10.1158/1541-7786.MCR-13-0131