Low Expression of RGS2 Promotes Poor Prognosis in High-Grade Serous Ovarian Cancer

SIMPLE SUMMARY: Recent advances in molecular medicine have indicated G-protein coupled receptors (GPCRs) as possible therapeutic targets in ovarian cancer. The cellular effects of GPCRs are determined by regulator of G protein signaling (RGS) proteins. Especially RGS2 has currently moved into focus of cancer therapy. Therefore, we retrospectively analyzed RGS2 and its association with the prognosis of high-grade serous ovarian cancer (HGSOC). Here, we provide in situ and in silico analyses regarding the expression patterns and prognostic value of RGS2. In silico we found that RGS2 is barely detectable in tumor cells on the mRNA level in bulk and single-cell data. Applying immunohistochemistry in 519 HGSOC patients, we detected moderate to strong protein expression of RGS2 in situ in approximately half of the cohort, suggesting regulation by post translational modification. Furthermore, low protein expression of RGS2 was associated with an inferior overall- and progression-free survival. These results warrant further research of its role and related new therapeutic implications in HGSOC. ABSTRACT: RGS2 regulates G-protein signaling by accelerating hydrolysis of GTP and has been identified as a potentially druggable target in carcinomas. Since the prognosis of patients with high-grade serous ovarian carcinoma (HGSOC) remains utterly poor, new therapeutic options are urgently needed. Previous in vitro studies have linked RGS2 suppression to chemoresistance in HGSOC, but in situ data are still missing. In this study, we characterized the expression of RGS2 and its relation to prognosis in HGSOC on the protein level by immunohistochemistry in 519 patients treated at Charité, on the mRNA level in 299 cases from TCGA and on the single-cell level in 19 cases from publicly available datasets. We found that RGS2 is barely detectable on the mRNA level in both bulk tissue (median 8.2. normalized mRNA reads) and single-cell data (median 0 normalized counts), but variably present on the protein level (median 34.5% positive tumor cells, moderate/strong expression in approximately 50% of samples). Interestingly, low expression of RGS2 had a negative impact on overall survival (p = 0.037) and progression-free survival (p = 0.058) on the protein level in lower FIGO stages and in the absence of residual tumor burden. A similar trend was detected on the mRNA level. Our results indicated a significant prognostic impact of RGS2 protein suppression in HGSOC. Due to diverging expression patterns of RGS2 on mRNA and protein levels, posttranslational modification of RGS2 is likely. Our findings warrant further research to unravel the functional role of RGS2 in HGSOC, especially in the light of new drug discovery.