Knockdown of hypoxia-inducible factor-1α in breast carcinoma MCF-7 cells results in reduced tumor growth and increased sensitivity to methotrexate
Knockdown of hypoxia-inducible factor-1α in breast carcinoma MCF-7 cells results in reduced tumor growth and increased sensitivity to methotrexate
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DOI：
10.1016/j.bbrc.2006.02.094
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发表时间：
2006-04-21
影响因子：
3.1
通讯作者：
Zhao, RCH
中科院分区：
文献类型：
--
作者：
Li, J;Shi, MX;Zhao, RCH
缺氧诱导因子（HIF）1 α a是细胞对缺氧反应的关键调节因子。特异性破坏HIF-1通路对于探索其在肿瘤生物学中的作用和开发更有效的治疗癌症的武器非常重要。在这项研究中，我们稳定转染人乳腺癌MCF-7细胞与短发夹RNA表达载体靶向HIF-1 α。敲低HIF-1 α后，其靶基因如血管内皮生长因子、Glut-1、磷酸甘油酸激酶和P-糖蛋白的缺氧诱导表达显著减弱。此外，发现HIF-α敲低可抑制缺氧诱导的S期向G（1）期的转变，并增加对甲氨蝶呤的药物敏感性。在皮下和原位异种移植模型中，HIF 1 α敲低肿瘤的生长速率均显著减慢，并伴有组织切片中血管生成减少和葡萄糖转运蛋白表达减少。这些数据表明，HIF-1 α敲低降低了MCF-7细胞的致瘤性，并提出了一种有希望的抗HIF-1策略和传统化疗的组合，以改善癌症治疗。(c)2006年爱思唯尔公司All rights reserved.
The hypoxia-inducible factor (HIF) 1 alpha a is a key regulator of the cellular response to oxygen deprivation. Specific disruption of the HIF-1 pathway is important for exploring its role in tumor biology and developing more efficient weapons to treat cancer. In this study, we stably transfected human breast tumor MCF-7 cells with short hairpin RNA expression vectors targeting HIF-1 alpha. After knockdown of HIF-1 alpha, hypoxia-induced expression of its target genes such as vascular endothelial growth factor, Glut-1, phosphoglycerate kinase, and P-glycoprotein were markedly attenuated. Moreover, HIF-alpha knockdown was found to suppress the shift from S-phase to G(1) induced by hypoxia and increase drug sensitivity to methotrexate. The growth rates of HIF1 alpha-knockdown tumors were drastically retarded in both Subcutaneous and orthotopic xenograft models, which were accompanied by decreased angiogenesis and reduced expression of glucose transporter in tissue sections. These data demonstrate that HIF-1 alpha knockdown reduces tumorigenicity of MCF-7 cells and Suggest a promising combination of both anti-HIF-1 strategy and traditional chemotherapy to improve cancer treatment. (c) 2006 Elsevier Inc. All rights reserved.