Abstract
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.
Highlights
Ovarian cancer has the highest mortality rate among gynecological cancers with a five-year overall survival (OS) rate remains as low as 30% - 40% in these two decades [1,2,3]
By using RNA sequencing, we found that Exocrine Differentiation and Proliferation Factor (EXDPF) is higher expressed in ovarian tumors compared to normal ovarian tissues from the same 3 patients (Figure 1A)
Using the Human Protein Atlas online database, this study showed that ovarian cancer had one of the highest mRNA expression levels of EXDPF among 17 tested tumors, while normal ovarian tissues had weak or low expression of EXDPF among 36 normal human tissues (Figure 1D)
Summary
Ovarian cancer has the highest mortality rate among gynecological cancers with a five-year overall survival (OS) rate remains as low as 30% - 40% in these two decades [1,2,3]. PARP inhibitors, both FDA approved and under clinical trials, could increase 3 to 25 months of median progression-free survival (PFS) of ovarian cancer patients with a better response in BRCA mutated patients in clinical trials [9,10,11], less efficacy of PARP inhibitors on OS of ovarian cancer patients could be observed [12]. Three PARP inhibitors, Olaparib, Rucaparib and Niraparib, are approved by U.S FDA to treat ovarian cancer patients. These PARP inhibitors could only increase 2% - 4% of OS, which is just about 2-5 months [13,14,15]. The worse situation is that only 6% to 15% of ovarian cancer patients respond to PD-1 and/or PDL-1 blockade therapies [18, 19]
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