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.
Authors' Affiliations: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine; Neurosurgery Department of Huashan Hospital, Fudan University; Shanghai Lung Tumor Clinical Medical Center, Chest Hospital Affiliated to Shanghai Jiao Tong University; Laboratory of Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, PR China; and Department of Dermatology, Duke University Medical Center, Durham, North Carolina.
Min
M
Zhou
Hai
H
Wang
Keke
K
Zhou
Xiaoying
X
Luo
Xiaorong
X
Pan
Bizhi
B
Shi
Hua
H
Jiang
Jiqin
J
Zhang
Kesang
K
Li
Hua-Mao
HM
Wang
Huiping
H
Gao
Shun
S
Lu
Ming
M
Yao
Ying
Y
Mao
Hong-Yang
HY
Wang
Shengli
S
Yang
Jianren
J
Gu
Chuanyuan
C
Li
Zonghai
Z
Li
D000818:Animals; D002465:Cell Movement / Q000235:genetics; D066246:ErbB Receptors / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D020033:Protein Isoforms / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D020033:Protein Isoforms; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D066246:ErbB Receptors