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.
Jiang
H
H
Department of Obstetrics and Gynecologic Hospital of Fudan University, Shanghai, China.
Feng
Y
Y
D000199:Actins / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D008833:Microcirculation; D009130:Muscle, Smooth; D009389:Neovascularization, Pathologic; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000451:nursing / Q000503:physiopathology; D010053:Ovary / Q000098:blood supply; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D020123:Sirolimus / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
D000199:Actins; D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D042461:Vascular Endothelial Growth Factor A; D017239:Paclitaxel; D020123:Sirolimus