Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers.
Hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers.
复制标题
缺氧引起的肺癌中PTEN活性和EMT表型的调节。
DOI：
10.1186/s12935-016-0308-3
复制
发表时间：
2016
影响因子：
5.8
通讯作者：
Hasegawa Y
中科院分区：
文献类型：
--
作者：
Kohnoh T;Hashimoto N;Ando A;Sakamoto K;Miyazaki S;Aoyama D;Kusunose M;Kimura M;Omote N;Imaizumi K;Kawabe T;Hasegawa Y
持续低氧刺激是最关键的微环境因素之一，可加速肺癌细胞上皮间质转化（EMT）表型的获得。10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）表达的缺失可能加速体内肺癌的发展。最近的研究表明，肿瘤微环境因素可能通过降低总的PTEN表达和增加PTENC-末端（p-PTEN）的磷酸化来调节PTEN活性，从而导致EMT表型的获得。然而，目前尚不清楚持续缺氧是否可以调节PTEN磷酸酶活性或缺氧诱导的EMT表型是否受到PTEN磷酸酶活性的负调控。我们的目的是研究低氧诱导的肺癌中PTEN活性和EMT表型的调节。在五种肺癌细胞系中进行蛋白质印迹以评估总PTEN表达水平和PTEN活化。在具有内源性PTEN表达的肺癌细胞的异种移植物模型中，通过免疫组织化学评估PTEN表达。为了检测缺氧对体外肺癌细胞表型改变的影响，将细胞在缺氧下培养。通过使用Dox依赖的基因表达系统，评估未磷酸化的PTEN（PTEN 4A）诱导对缺氧诱导的EMT表型的影响。涉及EMT表型的肺癌细胞显示总PTEN表达减少和p-PTEN表达增加。在异种移植模型中，在显示组织缺氧的肿瘤病变中观察到PTEN表达的丧失。持续缺氧在体外产生约8倍的p-PTEN/PTEN比率增加。PTEN 4A不影响缺氧诱导因子1α的稳定性。PTEN 4A通过抑制β-catenin向细胞质和细胞核的转位来减弱缺氧诱导的EMT。我们的研究加强了治疗的可能性，即非磷酸化的PTEN的补偿诱导可能会抑制在持续缺氧下肺癌细胞获得EMT表型。
Persistent hypoxia stimulation, one of the most critical microenvironmental factors, accelerates the acquisition of epithelial–mesenchymal transition (EMT) phenotypes in lung cancer cells. Loss of phosphatase and tensin homologue deleted from chromosome 10 (PTEN) expression might accelerate the development of lung cancer in vivo. Recent studies suggest that tumor microenvironmental factors might modulate the PTEN activity though a decrease in total PTEN expression and an increase in phosphorylation of the PTEN C-terminus (p-PTEN), resulting in the acquisition of the EMT phenotypes. Nevertheless, it is not known whether persistent hypoxia can modulate PTEN phosphatase activity or whether hypoxia-induced EMT phenotypes are negatively regulated by the PTEN phosphatase activity. We aimed to investigate hypoxia-induced modulation of PTEN activity and EMT phenotypes in lung cancers. Western blotting was performed in five lung cancer cell lines to evaluate total PTEN expression levels and the PTEN activation. In a xenograft model of lung cancer cells with endogenous PTEN expression, the PTEN expression was evaluated by immunohistochemistry. To examine the effect of hypoxia on phenotypic alterations in lung cancer cells in vitro, the cells were cultured under hypoxia. The effect of unphosphorylated PTEN (PTEN4A) induction on hypoxia-induced EMT phenotypes was evaluated, by using a Dox-dependent gene expression system. Lung cancer cells involving the EMT phenotypes showed a decrease in total PTEN expression and an increase in p-PTEN. In a xenograft model, loss of PTEN expression was observed in the tumor lesions showing tissue hypoxia. Persistent hypoxia yielded an approximately eight-fold increase in the p-PTEN/PTEN ratio in vitro. PTEN4A did not affect stabilization of hypoxia-inducible factor 1α. PTEN4A blunted hypoxia-induced EMT via inhibition of β-catenin translocation into the cytoplasm and nucleus. Our study strengthens the therapeutic possibility that compensatory induction of unphosphorylated PTEN may inhibit the acquisition of EMT phenotypes in lung cancer cells under persistent hypoxia.