Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer.
Overexpression of the EGF receptor (EGFR) is a recurrent theme in human cancer and is thought to cause aggressive phenotypes and resistance to standard therapy. There has, thus, been a concerted effort in identifying EGFR gene mutations to explain misregulation of EGFR expression as well as differential sensitivity to anti-EGFR drugs. However, such genetic alterations have proven to be rare occurrences in most types of cancer, suggesting the existence of a more general physiological trigger for aberrant EGFR expression. Here, we provide evidence that overexpression of wild-type EGFR can be induced by the hypoxic microenvironment and activation of hypoxia-inducible factor 2-alpha (HIF2alpha) in the core of solid tumors. Our data suggest that hypoxia/HIF2alpha activation represents a common mechanism for EGFR overexpression by increasing EGFR mRNA translation, thereby diminishing the necessity for gene mutations. This allows for the accumulation of elevated EGFR levels, increasing its availability for the autocrine signaling required for tumor cell growth autonomy. Taken together, our findings provide a nonmutational explanation for EGFR overexpression in human tumors and highlight a role for HIF2alpha activation in the regulation of EGFR protein synthesis.
Franovic
Aleksandra
A
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada K1H 8M5.
Gunaratnam
Lakshman
L
Smith
Karlene
K
Robert
Isabelle
I
Patten
David
D
Lee
Stephen
S
D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D000099162:Endothelial PAS Domain-Containing Protein 1