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The Exocrine Differentiation and Proliferation Factor (EXDPF) gene could promote exocrine while inhibit endocrine functions. Although it is well known that ovary is an endocrine organ, the functions of EXDPF in ovarian cancer development is still unknown. This study demonstrated that EXDPF gene is significantly higher expressed in ovarian tumors compared to normal ovarian tissue controls. EXDPF DNA amplification was exhibited in lots of human tumors including 7.19% of ovarian tumors. Also, high expression of EXDPF positively correlated with poor overall survival (OS) of ovarian cancer patients. EXDPF expression could be universally detected in most epithelial ovarian cancer cells (SKOV3, IGROV1, MACS, HO8910PM, ES2, COV362 and A2780) tested in this study. Knock-down of EXDPF by siRNA delivered by plasmid or lentivirus largely inhibited ovarian cancer cells, IGROV1 and SKOV3 proliferation, migration and tumorigenesis in vitro and/or in vivo. Knock-down of EXDPF sensitized SKOV3 cells to the treatment of the front-line drug, paclitaxel. Mechanism study showed that EXDPF enhanced DNA replication pathway to promote ovarian cancer tumorigenesis. In conclusion, this study demonstrated that EXDPF could be a potential therapeutic target as a pro-oncogene of ovarian cancer.

Novel inhibitors are urgently needed for use as targeted therapies to improve the overall survival (OS) of patients with ovarian cancer. Here, we show that cell division cycle 25B (CDC25B) is over-expressed in ovarian tumors and associated with poor patient prognosis. All previously reported CDC25B inhibitors have been identified by their ability to reversibly inhibit the catalytic dephosphorylation activity of CDC25B in vitro; however, none of these compounds have entered clinical trials for ovarian cancer therapy. In this study, we synthesized a novel small molecule compound, WG-391D, that potently down-regulates CDC25B expression without affecting its catalytic dephosphorylation activity. The inhibition of CDC25B by WG-391D is irreversible, and WG-391D should therefore exhibit potent antitumor activity against ovarian cancer. WG-391D induces cell cycle progression arrest at the G2/M phase. Half maximal inhibitory concentration (IC50) values of WG-391D for inhibition of the proliferation and migration of eight representative ovarian cancer cell lines (SKOV3, ES2, OVCAR8, OVTOKO, A2780, IGROV1, HO8910PM, and MCAS) and five primary ovarian tumor cell lines (GFY004, GFY005, CZ001, CZ006, and CZ008) were lower than 10 and 1 μM, respectively. WG-391D inhibited tumor growth in nude mice inoculated with SKOV3 cells or a patient-derived xenograft (PDX). The underlying mechanisms were associated with the down-regulation of CDC25B and subsequent inactivation of cell division cycle 2 (CDC2) and the serine/threonine kinase, AKT. In conclusion, this study demonstrates that WG-391D exhibits strong antitumor activity against ovarian cancer and indicates that the down-regulation of CDC25B by inhibitors could provide a rationale for ovarian cancer therapy.