The role of RNA-binding motif 3 in epithelial ovarian cancer: A biomarker discovery approach

Abstract: Epithelial ovarian cancer (EOC) is the most lethal of all gynaecological malignancies and there is an urgent need to develop new prognostic and treatment predictive biomarkers for a more efficient therapy. The discovery of the RNA-binding motif protein 3 (RBM3) as a putative cancer biomarker was based on its differential expression in various cancer forms in the Human Protein Atlas (HPA). Further investigations demonstrated an association between high nuclear RBM3 expression and improved survival in breast cancer. In this thesis, the prognostic value of RBM3 was examined at the mRNA and protein levels in two independent EOC cohorts, whereby increased expression of RBM3 was found to be associated with a favorable prognosis. Further in vitro studies revealed a sensitizing effect of RBM3 to the platinum compound cisplatin. With the aim to indentify underlying biological processes associated with RBM3 expression in EOC we performed a gene set enrichment analysis and uncovered an association between RBM3 expression and several cellular processes involved in the maintenance of DNA integrity, including DNA replication, chromatin remodeling and DNA integrity checkpoint. The RBM3 regulated genes were subsequently screened in the HPA and proteins displaying a differential expression pattern among EOC samples were further analyzed in EOC cell lines. An inverse correlation was observed between RBM3 and MCM3, Chk1 and Chk2. The prognostic value of theses markers was investigated in two EOC cohorts revealing an association between Chk1, Chk2 and MCM3 expression and an impaired survival. In addition, we investigated a possible involvement of RBM3 in the cell cycle process and observed a delay in S-phase progression upon downregulation of RBM3 in a synchronized cell population, suggesting a possible role of RBM3 in DNA replication.