期刊
CANCER RESEARCH
卷 73, 期 23, 页码 7056-7067出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-0194
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资金
- National Natural Science Foundation of China [81071746, 81101665, 31000565]
- Key Program Project of the Shanghai Science and Technology Committee [10431903700]
- Supporting Program of the Twelfth Five-year Plan for Science and Technology Research of China [2012ZX09103-301-005]
- Grant-in-Aid for Young Scientists Foundation of the Shanghai Cancer Institute [SB10-01]
- Research fund of the state key laboratory of oncogenes and related genes [91-11-03]
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. (C)2013 AACR.
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