Research on the process and molecular mechanism of inhibiting serous ovarian cancer by PRTN3 and its inhibitor Sivelestat.

Abstract

Background: Serous ovarian cancer (SOC) is one of the most important diseases affecting women's health in the world. It is highly occult and often detected in late stage due to the lack of specific molecular markers.

Methods: Whole exon sequencing was performed on 38 serous ovarian cancer samples, and the mutated gene PRTN3 was selected by bioinformatics analysis. In vitro experiments with serous ovarian cancer cell lines SKOV3 and OVCAR8 and normal ovarian epithelial cell line IOSE80 were performed to verify the expression of PRTN3 and the effect of its inhibitor sivelestat. Xenotransplantation models in vivo also confirmed the effect of sivelestat.

Result: We found that Missense Mutation accounted for the vast majority of somatic mutations, and 263 candidate mutant genes were obtained from the mutation frequency, among which three hub gene clusters centered on SF3A2, MUC3A, and PRTN3 were identified, and PRTN3 had the strongest effect on the overall survival of the patients. Subsequently, we verified the expression of PRTN3 in serous ovarian cancer samples and cell lines, PRTN3 was highly expressed in serous ovarian cancer samples and cell lines, and sivelestat could inhibit the migration ability of serous ovarian cancer cell lines. SKOV3 cells were used to construct xenografted tumor models to explore the prospect of PRTN3 as a molecular therapeutic target for ovarian cancer and the application potential of sivelestat, which can inhibit the progression of xenografted tumors in vivo with certain safety.

Conclusions: Whole exome sequencing and bioinformatics analysis identified PRTN3 as a potential molecular marker of serous ovarian cancer, and PRTN3 could significantly affect the prognosis of SOC patients. As an inhibitor of PRTN3, sivelestat can inhibit the expression of PRTN3 in SOC cell lines and reduce their migration ability in vitro. In vivo experiments showed that sivelestat can inhibit the growth of subcutaneous transplanted tumor in nude mice with certain safety.