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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer
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Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer

机译：肿瘤缺氧对EGFR的翻译上调为人类癌症中的过表达提供了一种非突变的解释

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Overexpression of the EGF receptor (EGFR) is a recurrent theme in human cancer and is thought to cause aggressive phenotypes and resistance to standard therapy. There has, thus, been a concerted effort in identifying EGFR gene mutations to explain misregulation of EGFR expression as well as differential sensitivity to anti-EGFR drugs. However, such genetic alterations have proven to be rare occurrences in most types of cancer, suggesting the existence of a more general physiological trigger for aberrant EGFR expression. Here, we provide evidence that overexpression of wild-type EGFR can be induced by the hypoxic microenvironment and activation of hypoxia-inducible factor 2-α (HIF2α) in the core of solid tumors. Our data suggest that hypoxia/HIF2α activation represents a common mechanism for EGFR overexpression by increasing EGFR mRNA translation, thereby diminishing the necessity for gene mutations. This allows for the accumulation of elevated EGFR levels, increasing its availability for the autocrine signaling required for tumor cell growth autonomy. Taken together, our findings provide a nonmutational explanation for EGFR overexpression in human tumors and highlight a role for HIF2α activation in the regulation of EGFR protein synthesis.
机译：EGF受体（EGFR）的过表达是人类癌症中的复发主题，被认为会引起攻击性表型和对标准疗法的耐药性。因此，在鉴定EGFR基因突变方面做出了共同努力，以解释EGFR表达的失调以及对抗EGFR药物的差异敏感性。但是，已证明这种遗传改变在大多数类型的癌症中很少发生，这表明存在异常EGFR表达的更一般的生理触发因素。在这里，我们提供的证据表明，在实体瘤的核心中，低氧微环境和缺氧诱导因子2-α（HIF2α）的激活可以诱导野生型EGFR的过表达。我们的数据表明，缺氧/HIF2α激活通过增加EGFR mRNA的翻译来代表EGFR过表达的常见机制，从而减少了基因突变的必要性。这允许升高的EGFR水平的积累，增加其对于肿瘤细胞生长自主权所需的自分泌信号传导的可用性。综上所述，我们的发现为人类肿瘤中EGFR的过度表达提供了非突变的解释，并突出了HIF2α激活在EGFR蛋白合成调控中的作用。

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