Decreased RBPMS Levels Promote Cell Proliferation, Invasion, Angiogenesis, in Cisplatin Resistant Ovarian Cancer Cells

Abstract

RBPMS is a RNA binding protein with multiple splicing encoded by the RBPMS gene located in chromosome eight in humans. Three major RBPMS isoforms have been described, RBPMS-A (21.8 kDa), RBPMS-B (22.4 kDa) and RBPMS-C (24.2 kDa). Evidence indicate that RBPMS interact with c-Fos, a member of the AP-1 family, that include also c-Jun. Furthermore, RBPMS interact with SMAD protein members to regulate gene expression. Reports have shown that each RBPMS isoform interacts with proteins and/or RNAs responsible for cell growth, proliferation, and tumor progression. Previous reports of our laboratory have found that RBPMS expression decrease in cisplatin resistance compared with cisplatin sensitive cells. However, the specific RBPMS isoform responsible of this observation has not been elucidated and less is known about its role on invasiveness ability and angiogenesis capacity. We overexpressed each RBPMS-A and RBPMS-C in the cisplatin resistant ovarian cancer cells, A2780CP20, and performed cell viability, cell proliferation, invasion assay, and tumor growth in subcutaneous mouse models. Significant reduction in the number of colonies and their area were observed in both isoform A and isoform C of RBPMS compared with control clones. However, clones of isoform A but not the isoform C were more sensitive to cisplatin treatment. Furthermore, in vivo experiments showed a significant reduction in tumor growth between RBPMS A and C when compared with the controls. Tumor tissues were subjected to immunohistochemical analysis for proliferation (Ki67) and angiogenesis (CD31). Elevated signals of both antibodies were detected in tissues from control groups when compared with RBPMS A and C overexpressing tumor tissues. These results suggest that both, isoform A and C, regulate transcripts involved in cell proliferation and invasion capacity of ovarian cancer cells. However, only the isoform A contributed to the cisplatin sensitivity of ovarian cancer cells. Moreover, RBPMS represses uncontrolled proliferation, invasiveness, and angiogenesis in ovarian cancer cells. Future efforts on this project will be focused on determining the RBPMS isoform that represses AP-1 (c-Fos and c-Jun) dependent gene regulation in cisplatin sensitive ovarian cancer cells.