Hypoxia-inducible factor 1 promotes chemoresistance of lung cancer by inducing carbonic anhydrase IX expression.
Hypoxia-inducible factor 1 promotes chemoresistance of lung cancer by inducing carbonic anhydrase IX expression.
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低氧诱导因子1通过诱导碳酸酐酶IX表达来促进肺癌的化学耐药性。
DOI：
10.1002/cam4.991
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发表时间：
2017-01
期刊：
影响因子：
4
通讯作者：
Date H
中科院分区：
文献类型：
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作者：
Sowa T;Menju T;Chen-Yoshikawa TF;Takahashi K;Nishikawa S;Nakanishi T;Shikuma K;Motoyama H;Hijiya K;Aoyama A;Sato T;Sonobe M;Harada H;Date H
由于化疗耐药，肺癌治疗很困难。缺氧诱导因子1 （HIF‐1）和HIF‐1诱导的糖酵解与化疗耐药相关；然而，这在肺癌中并不明显。我们研究了HIF‐1α和碳酸酐酶IX (CAIX)（一种中和细胞内酸中毒的跨膜蛋白）对肺癌患者诱导放化疗后化疗耐药和预后的影响。利用体外常氧或缺氧条件下的A549肺癌细胞，研究了HIF‐1α、葡萄糖转运蛋白1 （GLUT1）和CAIX与肺癌化疗耐药的关系。研究了HIF‐1α‐诱导的A549细胞糖代谢途径重编程以及HIF‐1和CAIX对长春瑞滨细胞毒性的影响。采用免疫组化分析方法测定肺癌患者诱导放化疗后肿瘤标本中HIF‐1α、GLUT1和CAIX的表达水平。缺氧诱导A549细胞中HIF‐1α的表达。此外，缺氧以HIF‐1依赖性的方式诱导A549细胞中GLUT1和CAIX的表达。通过诱导HIF‐1α， A549细胞的糖代谢途径从氧化磷酸化转变为糖酵解。HIF‐1和CAIX诱导缺氧下的化疗耐药，其抑制作用恢复了A549细胞的化疗敏感性。HIF‐1α、GLUT1和CAIX的表达水平与诱导放化疗后肺癌患者较差的总生存率相关。HIF‐1和CAIX影响肺癌患者A549细胞的化疗敏感性和预后。因此，抑制HIF‐1和CAIX可能改善肺癌患者诱导放化疗后的预后。进一步的分析可能有助于开发肺癌的治疗方法。
Lung cancer treatment is difficult owing to chemoresistance. Hypoxia‐inducible factor 1 (HIF‐1) and HIF‐1‐induced glycolysis are correlated with chemoresistance; however, this is not evident in lung cancer. We investigated the effect of HIF‐1α and carbonic anhydrase IX (CAIX), a transmembrane protein neutralizing intracellular acidosis, on chemoresistance and prognosis of lung cancer patients after induction chemoradiotherapy. Associations of HIF‐1α, glucose transporter 1 (GLUT1), and CAIX with chemoresistance of lung cancer were investigated using A549 lung cancer cells under normoxia or hypoxia in vitro. HIF‐1α‐induced reprogramming of glucose metabolic pathway in A549 cells and the effects of HIF‐1 and CAIX on the cytotoxicity of vinorelbine were investigated. Immunohistochemical analyses were performed to determine HIF‐1α, GLUT1, and CAIX expression levels in cancer specimens from lung cancer patients after induction chemoradiotherapy. Hypoxia induced HIF‐1α expression in A549 cells. Moreover, hypoxia induced GLUT1 and CAIX expression in A549 cells in a HIF‐1‐dependent manner. Glucose metabolic pathway was shifted from oxidative phosphorylation to glycolysis by inducing HIF‐1α in A549 cells. HIF‐1 and CAIX induced chemoresistance under hypoxia, and their inhibition restored the chemosensitivity of A549 cells. The expression levels of HIF‐1α, GLUT1, and CAIX were associated with poor overall survival of lung cancer patients after induction chemoradiotherapy. HIF‐1 and CAIX affected the chemosensitivity of A549 cells and prognosis of lung cancer patients. Therefore, inhibition of HIF‐1 and CAIX might improve prognosis of lung cancer patients after induction chemoradiotherapy. Further analysis might be helpful in developing therapies for lung cancer.