Hypoxia-inducible Factor 1alpha (HIF-1alpha) Correlated with Tumor Growth and Apoptosis in Ovarian Cancer

The aims of this study were to investigate the hypoxia-inducible factor 1alpha (HIF-1alpha) protein inhibition and tumor growth by a molecular target of rapamycin inhibitor, rapamycin, in xenogeneic transplant model of ovarian cancer and to study the correlation of apoptosis with HIF-1alpha and vascular endothelial growth factor (VEGF) expression. Four groups of female nude mice were inoculated subcutaneous with SKOV-3 cells and treated with vehicle, rapamycin, paclitaxel, or rapamycin plus paclitaxel. The expressions of HIF-1alpha and VEGF and microvessel density (MVD) were assessed by immunohistochemistry. While messenger RNA (mRNA) expression of Glut1, bcl-2, and VEGF was studied by reverse transcription-polymerase chain reaction, and apoptosis of tumor cells was determined by terminal deoxynucleotidyl biotin-dUTP nick end labeling (TUNEL). The HIF-1alpha was expressed in epithelial ovarian cancer. There was a significant correlation between HIF-1alpha protein expression and VEGF or MVD. Tumor burden treated with rapamycin alone, rapamycin plus paclitaxel, and paclitaxel alone was reduced (47.91%, 51.03%, and 31.75%, respectively) compared with controls. The expression of HIF-1alpha was inhibited, and apoptotic index of tumor cell increased in rapamycin and rapamycin plus paclitaxel group. HIF-1alpha may upregulate VEGF expression both in mRNA and protein level. There is a positive correlation between HIF-1alpha and MVD. Rapamycin inhibits expression of HIF-1alpha and suppresses ovarian tumor growth. Our data suggested that a combination of HIF-1alpha inhibitor and chemotherapy could provide an effective approach for inhibiting tumor growth in ovarian cancer.