Bifunctional roles of survivin-AEx3 and surviyin-2B for susceptibility to apoptosis in endometrial carcinomas

摘要

Purpose Alternative splicing variants of survivin have different biological roles on cell kinetics. Here, we focused on the effects of different variants, including wild type (wt), survivin-AEx3, and survivin-2B, on apoptosis and cell proliferation in endometrial carcinomas (Em Cas). Methods Expression of survivin-wt, survivin-AEx3, and survivin-2B with reference to cell death and proliferation was investigated, using Em Ca cell lines and its clinical tissues.Results Ishikawa cells stably overexpressing either survivin-AEx3 (Surv-AEx3#34) or survivin-2B (Surv-2B#17) demonstrated considerably lower proliferative activity, along with up-regulation of p21wafI. After TNF-a treatment, Surv-AEx3#34 cells showed an increase in apoptotic cells, while the effects were relatively minor in Surv-2B#17 cells. In contrast, doxorubicin treatment resulted in increased apoptotic cells in Surv-2B#17 but not Surv-AEx3#34 cells, along with decreased expression of bcl-2 relative to bax. Control Ishikawa cells also showed relatively higher endogenous mRNA expression of survivin-AEx3 and survivin-2B during treatment of TNF-a and doxorubicin, respectively. In addition, exogenous over-expression of each survivin variant resulted in inhibition of other endogenous isoforms, indicating that the relative proportion may contribute to regulation of the splicing machinery. In clinical samples, level of survivin-AEx3 relative to either survivin-wt or survivin-2B was significantly higher in Em Cas than non-neoplastic lesions. Moreover, survivin-AEx3 and survivin-wt were positively correlated with apoptosis and cell proliferation, respectively, in Em Cas.Conclusions These findings provided evidence that the balance among expression level of survivin variants may contribute to modulation of cell kinetics in Em Ca cells.