Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer

Aleksandra Franovic, Lakshman Gunaratnam, Karlene Smith, Isabelle Robert, David Patten, Stephen Lee

Research output: Contribution to journalArticle

167 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)13092-13097
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number32
DOIs
StatePublished - Aug 7 2007
Externally publishedYes

Fingerprint

Epidermal Growth Factor Receptor
Up-Regulation
Neoplasms
Tumor Hypoxia
Autocrine Communication
Mutation
Protein Biosynthesis
Genes
Phenotype

Keywords

  • Hypoxia inducible factor
  • Receptor tyrosine kinase signaling
  • Tumor microenvironment
  • VHL

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. / Franovic, Aleksandra; Gunaratnam, Lakshman; Smith, Karlene; Robert, Isabelle; Patten, David; Lee, Stephen.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 32, 07.08.2007, p. 13092-13097.

Research output: Contribution to journalArticle

@article{1f0a945f466340e7bdbfa420e01b3cd4,
title = "Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer",
abstract = "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.",
keywords = "Hypoxia inducible factor, Receptor tyrosine kinase signaling, Tumor microenvironment, VHL",
author = "Aleksandra Franovic and Lakshman Gunaratnam and Karlene Smith and Isabelle Robert and David Patten and Stephen Lee",
year = "2007",
month = "8",
day = "7",
doi = "10.1073/pnas.0702387104",
language = "English (US)",
volume = "104",
pages = "13092--13097",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "32",

}

TY - JOUR

T1 - Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer

AU - Franovic, Aleksandra

AU - Gunaratnam, Lakshman

AU - Smith, Karlene

AU - Robert, Isabelle

AU - Patten, David

AU - Lee, Stephen

PY - 2007/8/7

Y1 - 2007/8/7

N2 - 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.

AB - 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.

KW - Hypoxia inducible factor

KW - Receptor tyrosine kinase signaling

KW - Tumor microenvironment

KW - VHL

UR - http://www.scopus.com/inward/record.url?scp=34548803430&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548803430&partnerID=8YFLogxK

U2 - 10.1073/pnas.0702387104

DO - 10.1073/pnas.0702387104

M3 - Article

VL - 104

SP - 13092

EP - 13097

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 32

ER -