A Genome-Wide Search for Tumor Suppressor MicroRNAs in Ovarian Cancer

Ovarian cancer is one of the most lethal cancers among women. The Cancer Genome Atlas (TCGA) is a collaborative effort, which seeks to characterize the complete set of molecular changes associated with cancer and provide a public resource that will allow the development of new therapies and better diagnostic tools for cancer. Much of the focus is on protein coding genes and our understanding of the contribution from non-coding RNAs is lagging behind. MicroRNAs are small non-coding RNAs that can bind and repress hundreds of gene targets to regulate gene networks. Therefore, defining and understanding the miRNA-regulated genes offer new insights that can be clinically applied for many of the disease. In order to identify new tumor suppressors for ovarian cancer and downstream targets that drive key aspects of this disease such as drug resistance and metastatic spread, 3 candidates were selected from the microRNA-mRNA bioinformatic analyses from the TCGA. A combination of molecular and functional studies confirmed that miR-29a that can regulate genes from the histone modifier and cell cycle pathways, inhibit proliferation and moderately increase cisplatin response in the p53-WT HEYA8; miR-509-3p which targets genes from the ECM/EMT networks, inhibits cell proliferation in p53-WT HEYA8 and p53-mut OVCAR8 and correlated with improved overall survival when analyzed by in situ hybridization in an independent cohort; miR-130b increases apoptosis by 3-fold in p53-mutant OVCAR8 and p53-wild-type HEYA8 and significantly induces TAp63 and BCL2L11 (BIM). Forced expression of TAp63 decreases cell viability by 60-80% and miR-130b-ABT-737 (BCL2L11-mimetics) combination increases apoptosis by 9-fold suggesting TAp63 and BIM are critical effectors of the tumor-suppressive mechanisms driven by miR-130b, and can be used to develop new therapeutic strategies that will target p53 WT and p53 mutant tumors.Biology and Biochemistry, Department o