Epidermal growth factor receptor regulates MET levels and invasiveness through hypoxia-inducible factor-1alpha in non-small cell lung cancer cells.
Recent studies have established that amplification of the MET proto-oncogene can cause resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) cell lines with EGFR-activating mutations. The role of non-amplified MET in EGFR-dependent signaling before TKI resistance, however, is not well understood. Using NSCLC cell lines and transgenic models, we demonstrate here that EGFR activation by either mutation or ligand binding increases MET gene expression and protein levels. Our analysis of 202 NSCLC patient specimens was consistent with these observations: levels of MET were significantly higher in NSCLC with EGFR mutations than in NSCLC with wild-type EGFR. EGFR regulation of MET levels in cell lines occurred through the hypoxia-inducible factor (HIF)-1alpha pathway in a hypoxia-independent manner. This regulation was lost, however, after MET gene amplification or overexpression of a constitutively active form of HIF-1alpha. EGFR- and hypoxia-induced invasiveness of NSCLC cells, but not cell survival, were found to be MET dependent. These findings establish that, absent MET amplification, EGFR signaling can regulate MET levels through HIF-1alpha and that MET is a key downstream mediator of EGFR-induced invasiveness in EGFR-dependent NSCLC cells.
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
L
L
Xu
M B
MB
Nilsson
P
P
Saintigny
T
T
Cascone
M H
MH
Herynk
Z
Z
Du
P G
PG
Nikolinakos
Y
Y
Yang
L
L
Prudkin
D
D
Liu
J J
JJ
Lee
F M
FM
Johnson
K-K
KK
Wong
L
L
Girard
A F
AF
Gazdar
J D
JD
Minna
J M
JM
Kurie
I I
II
Wistuba
J V
JV
Heymach
D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D005784:Gene Amplification; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000502:physiology*; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D009361:Neoplasm Invasiveness; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000032:analysis / Q000235:genetics / Q000502:physiology*
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D017978:Receptors, Growth Factor; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met