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 differen...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-08, Vol.104 (32), p.13092-13097
Main Authors: Franovic, Aleksandra, Gunaratnam, Lakshman, Smith, Karlene, Robert, Isabelle, Patten, David, Lee, Stephen
Format: Article
Language:English
Subjects:
Basic Helix-Loop-Helix Transcription Factors - physiology
Biological Sciences
Cancer
Cell growth
Cell Hypoxia
Cell Line, Tumor
Cell lines
Gene expression
Gene Expression Regulation, Neoplastic
Genotype & phenotype
Humans
Hypoxia
Messenger RNA
Mutation
Neoplasms - metabolism
Neoplasms - pathology
Protein Biosynthesis
Protein synthesis
Receptor, Epidermal Growth Factor - genetics
Receptors
Small interfering RNA
Tumor cell line
Tumors
Up regulation
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Summary: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-α (HIF2α) in the core of solid tumors. Our data suggest that hypoxia/HIF2α 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 HIF2α activation in the regulation of EGFR protein synthesis.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0702387104