Effect of Hypoxia-inducible Factor-1α Silencing on the Sensitivity of Human Brain Glioma Cells to Doxorubicin and Etoposide
Effect of Hypoxia-inducible Factor-1α Silencing on the Sensitivity of Human Brain Glioma Cells to Doxorubicin and Etoposide
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DOI：
10.1007/s11064-008-9864-9
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发表时间：
2009-05-01
影响因子：
4.4
通讯作者：
Zhou, Dong
中科院分区：
文献类型：
--
作者：
Chen, Lei;Feng, Peimin;Zhou, Dong
多药耐药(MDR)是导致脑胶质瘤预后不良的一个重要问题。低氧诱导因子-1α(HIF-1α)被认为诱导多药耐药相关基因的表达。为评价缺氧诱导因子-1α(HIF-1α)对人脑胶质瘤T98G细胞的沉默作用，将HIF-1α-小干扰RNA(HIF-1α-siRNA)导入T98G细胞，在低氧条件下培养。检测HIF-1α-siRNA对HIF-1α和多药耐药相关蛋白1(MRP1)基因及蛋白水平的影响。HIF-1α基因转染后24、48、72 h的抑制率分别为90%、85%、88%。HIF-1α蛋白的符合率分别为74.5%、61.1%和59.1%。MRP1蛋白水平分别下降7.6%、36.8%和45.2%。HIF-1α-siRNA转染组细胞对阿霉素和依托泊苷的敏感性明显高于未转染组。这些发现表明，HIF-1α在神经胶质瘤细胞的化疗耐药中发挥了作用。HIF-1α沉默可能被证明是治疗胶质瘤的有效手段。
Multidrug resistance (MDR) is a significant problem underlying the poor prognosis associated with gliomas. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is thought to induce the genes expression involved in MDR. To evaluate the effect of silencing HIF-1 alpha in human glioma T98G cells, cells were transfected with HIF-1 alpha-small interference RNA (HIF-1 alpha-siRNA) and cultured under hypoxic conditions. The effect of HIF-1 alpha-siRNA on HIF-1 alpha and multidrug resistance-associated protein 1 gene (MRP1) and protein levels was determined. Silencing rates of HIF-1 alpha were 90%, 85%, and 88% at 24, 48, 72 h post-transfection, respectively. Corresponding rates of HIF-1 alpha protein were 74.5%, 61.1% and 59.1%. MRP1 protein levels decreased by 7.6%, 36.8% and 45.2%. HIF-1 alpha-siRNA transfected cells were significantly more sensitive to doxorubicin and etoposide compared to non-transfected cells. These findings suggest that the HIF-1 alpha plays a role in mediating chemotherapeutic drug resistance in glioma cells. HIF-1 alpha silencing may prove to be an effective therapeutic means of treating gliomas.