Loss of ITM2A, a novel tumor suppressor of ovarian cancer through G2/M cell cycle arrest, is a poor prognostic factor of epithelial ovarian cancer

Abstract

ObjectiveIntegral membrane protein 2A (ITM2A) is a type 2 transmembrane protein of unknown function. The aim of this study was to investigate its expression pattern, clinical significance, and biological function in epithelial ovarian cancer. MethodsITM2A expression in 35 normal, 20 adenoma, 11 borderline and 90 cancerous ovarian tissues was measured by immunohistochemistry. Clinicopathological parameters were obtained from medical records. Survival data was analyzed using Kaplan–Meier estimates and multivariate analysis using the Cox-regression method. Anti-tumor activities of ITM2A were explored by cell proliferation and colony formation assays, flow cytometry, Western blots and animal studies using ovarian cancer cell lines. Chemoresponsiveness was evaluated by measuring IC50 and confirmed by animal studies using an intraperitoneal orthotropic model. ResultsITM2A was significantly downregulated in invasive carcinomas compared to normal, adenoma and borderline tumor tissues. ITM2A loss occurred in 45.6% (41 of 90) of invasive carcinomas and was significantly associated with FIGO stage, type II tumors, suboptimal debulking operation, recurrence and chemoresistance. ITM2A loss and higher FIGO stage were independent factors for poor prognosis. Expression of ITM2A inhibited growth and induced G2/M cell cycle arrest by attenuating cdc2, cyclin B1, cdc25c and p-cdc2 (Thr 161). In vitro and in vivo experiments showed that ITM2A expression significantly reduced the paclitaxel and carboplatin IC50 and tumor mass after paclitaxel treatment. ConclusionITM2A is a new biomarker of poor prognosis in ovarian cancer. It is a novel tumor suppressor that induces cell cycle arrest, acts as a chemosensitizer, and has therapeutic potential for ovarian cancer.