Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer
Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer
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DOI：
10.1073/pnas.0702387104
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发表时间：
2007-08-07
影响因子：
11.1
通讯作者：
Lee, Stephen
中科院分区：
文献类型：
--
作者：
Franovic, Aleksandra;Gunaratnam, Lakshman;Lee, Stephen
EGF受体（EGFR）的过表达是人类癌症的一个复发主题，被认为会导致侵袭性表型和对标准治疗的耐药性。因此，在识别EGFR基因突变以解释EGFR表达失调以及对抗EGFR药物的不同敏感性方面，已经有了一致的努力。然而，这种基因改变已被证明在大多数类型的癌症中很少发生，这表明存在更普遍的EGFR异常表达的生理触发因素。在这里，我们提供了证据，证明在实体瘤的核心，缺氧微环境和缺氧诱导因子2- α (HIF2 α)的激活可以诱导野生型EGFR的过表达。我们的数据表明，缺氧/HIF2 α激活通过增加EGFR mRNA的翻译代表了EGFR过表达的共同机制，从而减少了基因突变的必要性。这允许EGFR水平升高的积累，增加了肿瘤细胞生长自主所需的自分泌信号的可用性。综上所述，我们的研究结果为人类肿瘤中EGFR过表达提供了一个非突变的解释，并强调了HIF2 α激活在调节EGFR蛋白合成中的作用。
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-alpha (HIF2 alpha) in the core of solid tumors. Our data suggest that hypoxia/HIF2 alpha 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 HIF2 alpha activation in the regulation of EGFR protein synthesis.