Upregulation of Wnt signaling under hypoxia promotes lung cancer progression
Upregulation of Wnt signaling under hypoxia promotes lung cancer progression
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DOI：
10.3892/or.2017.5807
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发表时间：
2017-09-01
期刊：
影响因子：
4.2
通讯作者：
Wu, Cheng-Wen
中科院分区：
文献类型：
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作者：
Hong, Chun-Fu;Chen, Wei-You;Wu, Cheng-Wen
低氧肿瘤微环境诱导肿瘤细胞中的上皮-间质转化（EMT）并增加肿瘤细胞恶性度。以往的研究表明，在一些肺癌患者中观察到Wnt信号传导障碍。尽管最近发现肿瘤细胞中缺氧和Wnt信号之间的串扰，但详细的潜在机制尚未得到很好的定义。在本研究中，我们证明肺腺癌细胞中的缺氧可以通过稳定β-连环蛋白并改变其在细胞核中的定位来增强Wnt信号传导活性。HIF-2 α的过表达增加β-连环蛋白的表达，促进细胞运动，并诱导形态学变化的程度大于HIF-1 α的过表达。HIF-2 α的敲低降低了β-连环蛋白的表达，并抑制了缺氧诱导的细胞运动。此外，我们确定，缺氧和HIF-2 α的磷酸化激活AKT 1是缺氧处理后Wnt激活所必需的。当细胞暴露于长期缺氧处理时，HIF-2 α和β-连环蛋白的下调减少了集落形成。总之，我们的数据支持缺氧以HIF-2 α依赖的方式激活PI 3 K/AKT以及Wnt信号，从而提高肺癌细胞对慢性缺氧诱导的应激的抵抗力。
The hypoxic tumor microenvironment induces epithelial-mesenchymal transition (EMT) in tumor cells and increases tumor cell malignancy. Previous studies indicated that malfunction of Wnt signaling is observed in some lung cancer patients. Athough crosstalk between hypoxia and Wnt signaling in tumor cells has recently been revealed, the detailed underlying mechanisms have not been well defined. In the present study, we demonstrated that hypoxia in lung adenocarcinoma cells can enhance Wnt signaling activity by stabilizing beta-catenin and altering its localization into the nucleus. Overexpression of HIF-2 alpha increased beta-catenin expression, promoted cell mobility, and induced morphological changes to a greater degree than HIF-1 alpha overexpression. Knockdown of HIF-2 alpha decreased beta-catenin expression and inhibited hypoxia-induced cell mobility. Moreover, we identified that phosphorylational activation of AKT1 by hypoxia and HIF-2 alpha was required for Wnt activation upon hypoxia treatment. Downregulation of HIF-2 alpha and beta-catenin reduced colony formation when cells were exposed to long-term hypoxia treatment. Taken together, our data support that hypoxia activates PI3K/AKT as well as Wnt signaling in a HIF-2 alpha-dependent manner, thus elevating the resistance of lung cancer cells to chronic hypoxia-induced stress.