The induction of MIG6 under hypoxic conditions is critical for dormancy in primary cultured lung cancer cells with activating EGFR mutations
The induction of MIG6 under hypoxic conditions is critical for dormancy in primary cultured lung cancer cells with activating EGFR mutations
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DOI：
10.1038/onc.2016.431
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发表时间：
2017-05-18
期刊：
影响因子：
8
通讯作者：
Inoue, M.
中科院分区：
文献类型：
--
作者：
Endo, H.;Okami, J.;Inoue, M.
单个癌细胞的生物活性是高度异质性的。缺氧是肿瘤微环境的突出特征之一，被认为是产生这种细胞异质性的原因。在这项研究中，我们发现，原发性肺癌细胞窝藏激活表皮生长因子受体（EGFR）突变一般进入休眠状态时，缺氧。我们发现ERBB家族受体酪氨酸激酶（RTK）的异二聚体形成及其随后的下游信号传导在缺氧条件下减少，尽管EGFR的磷酸化被保留。研究发现，肺腺癌细胞对EGFR酪氨酸激酶抑制剂（TKI）治疗具有耐药性。在机制方面，我们发现ERBB信号的负调节因子MIG 6/ERRFI 1/RALT/Gene 33在体外和体内均被缺氧诱导。MIG 6的表达阻止了ERBB家族RTK异二聚体的形成，并抑制了它们的下游信号传导。在低氧条件下，MIG 6的敲低增强了肿瘤细胞的生长，并通过增加EGFR-HER 3结合促进了ERK和AKT的磷酸化。重要的是，在MIG 6敲低细胞中，对EGFR-TKI以及对缺氧条件下的辐射的敏感性增加。在患者肿瘤中，MIG 6的表达与pS 6阴性区部分相关。对68例EGFR突变患者的肿瘤切片分析显示，高MIG 6表达患者在EGFR-TKI治疗后的生存期明显短于其他组。总的来说，我们的数据表明，具有高MIG 6表达水平的休眠癌细胞可能是EGFR突变型肺癌细胞中EGFR-TKI抗性的原因之一。
The biologic activity of individual cancer cells is highly heterogeneous. Hypoxia, one of the prominent features of a tumor microenvironment, is thought to be causal in generating this cellular heterogeneity. In this study, we revealed that primary lung cancer cells harboring activating epidermal growth factor receptor (EGFR) mutations generally entered a dormant state when hypoxic. We found that heterodimer formation of the ERBB family receptor tyrosine kinases (RTKs), and their subsequent downstream signaling, was diminished under hypoxic conditions, although phosphorylation of the EGFR was retained. Dormant lung cancer cells were found to be resistant to EGFR tyrosine kinase inhibitor (TKI) treatment. In terms of mechanism, we found that a negative regulator of ERBB signaling, MIG6/ERRFI1/RALT/Gene33, was induced by hypoxia both in vitro and in vivo. MIG6 expression prevented heterodimer formation of ERBB family RTKs, and suppressed their downstream signaling. Knockdown of MIG6 enhanced tumor cell growth under hypoxic conditions, and promoted the phosphorylation of ERK and AKT via increased EGFR-HER3 binding. Critically, sensitivity to an EGFR-TKI, as well as to irradiation under hypoxic conditions, was increased in MIG6 knockdown cells. The expression of MIG6 was partly correlated with a pS6 negative zone in patient tumors. Analyses of tumor sections from 68 patients with activating EGFR mutations showed that patients with high MIG6 expression showed significantly shorter survival after EGFR-TKI treatment than other groups. Collectively, our data suggest that dormant cancer cells with a high MIG6 expression level might be one of the causes of EGFR-TKI resistance in EGFR mutant lung cancer cells.