A Novel EGFR Isoform Confers Increased Invasiveness to Cancer Cells
A Novel EGFR Isoform Confers Increased Invasiveness to Cancer Cells
复制标题
一种新型 EGFR 亚型可增强癌细胞的侵袭性。
DOI：
10.1158/0008-5472.can-13-0194
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发表时间：
2013-12-01
期刊：
影响因子：
11.2
通讯作者：
Li, Zonghai
中科院分区：
文献类型：
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作者：
Zhou, Min;Wang, Hai;Li, Zonghai
作为几种人类癌症的有效治疗靶点，EGF受体（EGFR）为深入了解癌症病理生理学提供了一个焦点。在这项研究中，我们报告了一种天然存在的和广泛表达的EGFR亚型EGFRvA的鉴定，它取代了一个富含Ser/Thr的肽的受体的羧基末端调节结构域的一部分。有趣的是，EGFRvA表达与胶质瘤患者的组织病理学分级和不良预后更密切相关。EGFRvA在癌细胞中的异位表达在体外和体内赋予比EGFR更高的侵袭能力。从机制上讲，EGFRvA刺激STAT 3的表达，STAT 3上调肝素结合EGF（HB-EGF）。相反，HB-EGF刺激EGFRvA在Y845沿着STAT 3的磷酸化，产生一个正反馈环，可能加强侵袭功能。EGFRvA表达的重要性通过发现它被miR-542- 5 p减弱而得到加强，miR-542- 5 p是一种已知的肿瘤抑制因子。总之，我们的研究结果将这种新发现的EGFR亚型定义为关键的治疗诊断分子。
As a validated therapeutic target in several human cancers, the EGF receptor (EGFR) provides a focus to gain deeper insights into cancer pathophysiology. In this study, we report the identification of a naturally occurring and widely expressed EGFR isoform termed EGFRvA, which substitutes a Ser/Thr-rich peptide for part of the carboxyl-terminal regulatory domain of the receptor. Intriguingly, EGFRvA expression relates more closely to histopathologic grade and poor prognosis in patients with glioma. Ectopic expression of EGFRvA in cancer cells conferred a higher invasive capacity than EGFR in vitro and in vivo. Mechanistically, EGFRvA stimulated expression of STAT3, which upregulated heparin-binding EGF (HB-EGF). Reciprocally, HB-EGF stimulated phosphorylation of EGFRvA at Y845 along with STAT3, generating a positive feedback loop that may reinforce invasive function. The significance of EGFRvA expression was reinforced by findings that it is attenuated by miR-542-5p, a microRNA that is a known tumor suppressor. Taken together, our findings define this newfound EGFR isoform as a key theranostic molecule.