HIF-1α Mediates Tumor Hypoxia to Confer a Perpetual Mesenchymal Phenotype for Malignant Progression

Sci. Signal., 21 June 2011
Vol. 4, Issue 178, p. pt4
DOI: 10.1126/scisignal.2002072

HIF-1α Mediates Tumor Hypoxia to Confer a Perpetual Mesenchymal Phenotype for Malignant Progression

  1. Young-Gun Yoo1,
  2. Jared Christensen1,
  3. Jie Gu1, and
  4. L. Eric Huang1,2,*
  1. 1Department of Neurosurgery, University of Utah, Salt Lake City, UT 84132, USA.
  2. 2Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84132, USA.
  1. *Presenter and corresponding author. E-mail, eric.huang{at}hsc.utah.edu
A presentation from the Keystone Symposium on Epithelial Plasticity and Epithelial-to-Mesenchymal Transition, Vancouver, British Columbia, Canada, 21 to 26 January 2011.

Abstract

Although tumor progression involves genetic and epigenetic alterations to normal cellular biology, the underlying mechanisms of these changes remain obscure. Numerous studies have shown that hypoxia-inducible factor 1α (HIF-1α) is overexpressed in many human cancers and up-regulates a host of hypoxia-responsive genes for cancer growth and survival. We recently identified an alternative mechanism of HIF-1α function that induces genetic alterations by suppressing DNA repair. Here, we show that long-term hypoxia, which mimics the tumor microenvironment, drives a perpetual epithelial-mesenchymal transition (EMT) through up-regulation of the zinc finger E-box binding homeobox protein ZEB2, whereas short-term hypoxia induces a reversible EMT that requires the transcription factor Twist1. Moreover, we show that the perpetual EMT driven by chronic hypoxia depends on HIF-1α induction of genetic alterations rather than its canonical transcriptional activator function. These mesenchymal tumor cells not only acquire tumorigenicity but also display characteristics of advanced cancers, including necrosis, aggressive invasion, and metastasis. Hence, these results reveal a mechanism by which HIF-1α promotes a perpetual mesenchymal phenotype, thereby advancing tumor progression.

Citation:

Y.-G. Yoo, J. Christensen, J. Gu, and L. E. Huang, HIF-1α Mediates Tumor Hypoxia to Confer a Perpetual Mesenchymal Phenotype for Malignant Progression. Sci. Signal. 4, pt4 (2011).
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