HVEM/HIF-1α promoted proliferation and inhibited apoptosis of ovarian cancer cells under hypoxic microenvironment conditions

摘要

Our previous studies showed the expression of herpes virus entry mediator (HVEM) is high in ovarian cancer samples and correlated to the patient clinic pathological features. As we all know, the hypoxic environment is the main feature of tumor. In this work, we explored the role of HVEM in hypoxic ovarian cancer cells and its effects on HIF-1α, a transcription factor responding to hypoxia. The expression of HVEM, HIF-1α and apoptosis-related genes was detected by qRT-PCR and western blot. The proliferation and apoptosis of the ovarian cancer cells were determined with the Cell Counting Kit-8 assay and AnnexinV-FITC/PI-stained flow cytometry assay, respectively. The expression of HVEM was positively correlated to that of HIF-1α. The expression of HVEM and HIF-1α under hypoxic conditions was higher than that under normoxic conditions, which suggested that the level of HVEM and HIF-1α correlates with prolonged periods of hypoxia in ovarian cancer. The overexpression of HVEM promoted cell proliferation and inhibited cell apoptosis under hypoxic condition. HVEM overexpression elevated the expression of HIF-1α and Bcl-2 (anti-apoptotic protein), and reduced the expression of Bax (pro-apoptotic protein). In addition, overexpression of HVEM activated the AKT/mTOR signaling. Moreover, knockdown of HVEM had the completely opposite effects. These data indicated that HVEM signaling might promote HIF-1α activity via AKT/mTOR signaling pathway and thus to regulate tumor growth in ovarian cancer under the hypoxic conditions. Furthermore, these findings indicate that this molecular mechanism could represent a therapeutic target for ovarian cancer.