Hypoxia-inducible factor 1α (HIF-1α) correlated with tumor growth and apoptosis in ovarian cancer
Hypoxia-inducible factor 1α (HIF-1α) correlated with tumor growth and apoptosis in ovarian cancer
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DOI：
10.1111/j.1525-1438.2006.00310.x
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发表时间：
2006-01-01
影响因子：
4.8
通讯作者：
Feng, Y
中科院分区：
文献类型：
--
作者：
Jiang, H;Feng, Y
本研究旨在探讨雷帕霉素抑制剂分子靶点雷帕霉素在异种卵巢癌移植模型中对缺氧诱导因子1 α (HIF-1 α)蛋白的抑制作用与肿瘤生长的关系，并探讨HIF-1 α和血管内皮生长因子（VEGF）表达与细胞凋亡的关系。四组雌性裸鼠皮下接种SKOV-3细胞，分别给药、雷帕霉素、紫杉醇或雷帕霉素加紫杉醇。免疫组化法检测HIF-1 α、VEGF表达及微血管密度（MVD）。通过逆转录-聚合酶链反应研究Glut1、bcl-2和VEGF mRNA的表达，通过末端脱氧核苷酸生物素- dutp缺口末端标记法（TUNEL）检测肿瘤细胞凋亡情况。HIF-1 α在上皮性卵巢癌中表达。HIF-1 α蛋白表达与VEGF或MVD有显著相关性。与对照组相比，雷帕霉素单用组、雷帕霉素联合紫杉醇组和紫杉醇单用组的肿瘤负荷分别降低了47.91%、51.03%和31.75%。雷帕霉素组和雷帕霉素加紫杉醇组肿瘤细胞HIF-1 α表达受到抑制，肿瘤细胞凋亡指数升高。HIF-1 α可能在mRNA和蛋白水平上调VEGF的表达。HIF-1 α与MVD呈正相关。雷帕霉素抑制HIF-1 α的表达，抑制卵巢肿瘤的生长。我们的数据表明，HIF-1 α抑制剂联合化疗可为抑制卵巢癌肿瘤生长提供有效途径。
The aims of this study were to investigate the hypoxia-inducible factor 1 alpha (HIF-1 alpha) 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-1 alpha 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-1 alpha 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-1 alpha was expressed in epithelial ovarian cancer. There was a significant correlation between HIF-1 alpha 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-1 alpha was inhibited, and apoptotic index of tumor cell increased in rapamycin and rapamycin plus paclitaxel group. HIF-1 alpha may upregulate VEGF expression both in mRNA and protein level. There is a positive correlation between HIF-1 alpha and MVD. Rapamycin inhibits expression of HIF-1 alpha and suppresses ovarian tumor growth. Our data suggested that a combination of HIF-1 alpha inhibitor and chemotherapy could provide an effective approach for inhibiting tumor growth in ovarian cancer.