GPBAR1 Promotes Proliferation of Serous Ovarian Cancer by Inducing Smad4 Ubiquitination

Abstract

Background: Ovarian cancer (OC) is the most lethal malignancy of all female cancers and lacks an effective prognostic biomarker. Serous ovarian cancer (SOC) is the most common OC histologic type. The expression and function of bile acid receptor, G-protein-coupled bile acid receptor-1 (GPBAR1), in tumor progression remains controversial, and its clinical significance in SOC is unclear. Materials and Methods: In our study, we detected the expression of GPBAR1 in SOCs and normal ovarian tissues with quantitative real-time polymerase chain reaction and immunohistochemistry to detect its expression pattern. Moreover, the prognostic significance of GPBAR1 was investigated with univariate and multivariate analyses. The function of GPBAR1 in regulating SOC proliferation was studied and the underlying mechanism was investigated with experiments in vitro. Results: GPBAR1 was overexpressed in SOCs compared with the normal ovarian tissues. In the 166 SOCs, subsets with low and high GPBAR1 accounted for 57.23% and 42.77%, respectively. Moreover, our results suggested that GPBAR1 expression was significantly associated with poor prognosis and can be considered as an independent prognostic biomarker. With experiments in vitro, we suggested that GPBAR1 promoted SOC proliferation by increasing Smad4 ubiquitination, which required the involvement of GPBAR1-induced ERK phosphorylation. Conclusions: GPBAR1 was overexpressed in SOC and predicted the poor prognosis of SOC. We showed that GPBAR1 promoted SOC proliferation by activating ERK and ubiquitining Smad4. Our results suggested that GPBAR1 was a supplement to better classify SOC on the basis of the molecular profile and that GPBAR1 may be a potential drug target of SOC.