A novel EGFR isoform confers increased invasiveness to cancer cells.
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.
Mesh Terms:
Animals, Cell Movement, ErbB Receptors, HEK293 Cells, Humans, Mice, NIH 3T3 Cells, Neoplasm Invasiveness, Neoplasms, Prognosis, Protein Isoforms, STAT3 Transcription Factor, Signal Transduction, Survival Analysis, Tumor Cells, Cultured
Animals, Cell Movement, ErbB Receptors, HEK293 Cells, Humans, Mice, NIH 3T3 Cells, Neoplasm Invasiveness, Neoplasms, Prognosis, Protein Isoforms, STAT3 Transcription Factor, Signal Transduction, Survival Analysis, Tumor Cells, Cultured
Cancer Res.
Date: Dec. 01, 2013
PubMed ID: 24240702
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