ABSTRACT
BACKGROUND: Current prognostic information in ovarian cancer is based on tumor stage, tumor grade, and postoperative tumor size. Reliable molecular prognostic markers are scarce. In this article, the authors describe epigenetic events in a frequently deleted region on chromosome 8p22 that influence the expression of tumor suppressor candidate 3 (TUSC3), a putative tumor suppressor gene in ovarian cancer. METHODS: Messenger RNA expression and promoter hypermethylation of TUSC3 were studied in ovarian cancer cell lines and in tumor samples from 2 large, independent ovarian cancer cohorts using polymerase chain reaction-based methods. RESULTS: The results indicated that TUSC3 expression is decreased significantly because of promoter methylation in malignant ovarian tumors compared with benign controls. Almost 33% of ovarian cancer samples had detectable TUSC3 promoter methylation. Furthermore, methylation status of the TUSC3 promoter had a significant and independent influence on progression-free and overall survival. CONCLUSIONS: TUSC3 hypermethylation predicted progression-free and overall survival in ovarian cancer. The current observations suggested a role for N-glycosylating events in ovarian cancer pathogenesis in general and identified the epigenetic silencing of TUSC3 as a prognostic factor in this disease.
Subject(s)
DNA Methylation , Membrane Proteins/genetics , Ovarian Neoplasms/genetics , Tumor Suppressor Proteins/genetics , Adult , Cell Line, Tumor , Disease-Free Survival , Female , Genes, Tumor Suppressor , Humans , Middle Aged , Ovarian Neoplasms/mortality , Prognosis , Promoter Regions, GeneticABSTRACT
OBJECTIVE: Transforming growth factor beta (TGF-beta) signaling via Smads plays a central role in carcinogenesis. Bmp and activin membrane-bound inhibitor (BAMBI) was initially described as a pseudoreceptor antagonizing TGF-beta receptor activation, thus impairing signaling. Here we wanted to estimate the role of BAMBI in ovarian cancer. METHODS: The function of BAMBI was studied using a cell line model and intracellular localization experiments. The impact of BAMBI expression on patient outcome was estimated by real-time PCR and immunohistochemistry. RESULTS: We demonstrate for the first time a nuclear co-translocation of BAMBI with Smad2/3 upon TGF-beta treatment. Moreover, overexpression of BAMBI in an in vitro model led to significantly increased proliferation (doubling time -37.0%, P=0.010), migration (+581.2%, P=0.004) and resistance to TGF-beta-mediated apoptosis (decrease of apoptosis from 30% in the control cells to 7% in the BAMBI-overexpressing cells). Although-prima facie-this fits to the thesis of BAMBI as a pseudoreceptor, it may also be explained by modulation of TGF-beta signaling in the nucleus, leading to the observed pro-oncogenic properties. The tumor promoting impact of BAMBI mRNA overexpression in vitro could not be confirmed in primary tumor samples, and while nearly all tumor samples showed up-regulation of BAMBI (37.3% 1+, 39.2% 2+, and 16.7% 3+, respectively) compared to undetectable BAMBI in healthy pre- and post-menopausal ovarian epithelia, no impact of BAMBI expression on recurrence free and overall survival could be observed. CONCLUSION: These findings provide new insights into the Smad-mediated pathway by inferring that BAMBI is a novel modulator of TGF-beta signaling.
