Role of hypoxic response in tumor progression and metastasis
Research Interests: Hypoxic microenvironments are frequently found in solid tumors as a result of an imbalance between oxygen supply and consumption. Tumor hypoxia is a major therapeutic concern since it reduces the effectiveness of radiotherapy and some oxygen-dependent cytotoxic agents. More recently, hypoxia has been shown to be a driving force for malignant progression by hypoxia-inducible factor (HIF)-mediated activation of angiogenesis, anaerobic metabolism, and other processes that enable tumor cells to survive or escape their oxygen-deficient environment. Since this pathway operates in almost all solid malignancies, understanding the function and regulation of HIF will have a broad impact on cancer biology.
Transcriptional responses to hypoxia are primarily mediated by hypoxia inducible factors
(HIFs), HIF-1a and
HIF-2a.
HIF-1a and
HIF-2a exhibit several important similarities,
however, there is growing evidence indicating that the individual contributions of
HIF-1a and
HIF-2a in tumor progression are different.
To distinguish the role of HIF-1aand
HIF-2a in cancer progression, our work has been
focusing on these specific areas:
- What are the unique and common target genes of HIF-1a and HIF-2a?
- What is the individual role of HIF-1a and HIF-2a in cancer progression?
- What are the factors controlling HIF transcriptional activity?
We have completed target gene studies, which demonstrated that
HIF-1a and
HIF-2a have their unique targets (Hu et al., 2003).
For example, glycolytic genes are exclusively activated by
HIF-1a while
HIF-2a uniquely regulates genes involved in
angiogenesis (VEGF), cell proliferation (cyclin D1, PDGF, and
TGFa) and extracellular matrix metabolism
(MMP-2 and PAI-1). These studies suggest a critical role of
HIF-2a in tumor progression and metastasis.
We are currently deleting or over-expressing HIF-2a
in mouse strains that have head-and-neck cancers to investigate the roles of HIF in tumor progression and
metastasis.
We determined that HIF-1a and
HIF-2a require distinct transcriptional cofactors for
their transcriptional activity (Hu et al., 2006). We are investigating the factors that are required for general
or promoter-specific transcriptional activity of
HIF-1a and
HIF-2a. Understanding the interactions between HIF
and its cofactors will lay down a foundation to specifically block HIF general transcritpional activity or HIF's
regulation of a particular gene.
Selected Publications
Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1 alpha (HIF-1a) and HIF-2a in hypoxic gene regulation. Mol Cell Biol 2003 23:9361-9374.
Hu CJ, Iyer S, Sataur A, Covello KL, Chodosh LA, Simon MC. Differential regulation of the transcriptional activities of hypoxia-inducible factor 1 alpha (HIF-1a) and HIF-2a in stem cells. Mol Cell Biol 2006 26:3514-3526.
Covello KL, James K, Yu HW, Gordan JD, Arsham AM, Hu CJ, Labosky PA, Simon MC, Keith B. HIF-2a regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 2006 20:557-570.
Hu CJ, Sataur A, Wang LY, Simon MC. N-terminal transactivaton domain confers target gene specificity of hypoxia inducible factors. Submitted 2007.
Diez H, Fischer A, Hu CJ, Hatzopoulos A, Breier G, Gessler M. Hypoxia mediates activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate. Exp Cell Res 2007 313:1-9.
Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2? promotes proliferation under hypoxia by enhancing c-Myc transcriptional activity. Cancer Cell 2007 11:335-347.
Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MC. Acute postnatal ablation of HIF-2a results in anemia. Proc Natl Acad Sci USA 2007 104(7):2301-2306.
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