Cheng-Jun Hu Lab
Mail Stop 8120, RC1-S, Rm L18 11103
12801 E. 17th Ave
P.O. Box 6511
Aurora, CO 80045
Role of hypoxia response in tumor progression and metastasis 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. Emerging evidence indicates that the effect of hypoxia on malignant progression is mainly controlled 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. Conseuqently, HIF wil promote the selection and expansion of more aggressive clones of cancer cells. 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 (see Figure 1), 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-1a and HIF-2a in cancer progression, our work has been focusing on these specific areas:
1. What are the unique and common target genes of HIF-1a and HIF-2a?
2. What is the individual role of HIF-1a and HIF-2a in cancer progression?
3. 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 TGF-a), 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.
1. 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.
2. Hu CJ, Sataur A, Iyer S, 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.
3. 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 gorwth. Genes Dev 2006 20:557-570.
4. Hu CJ, Sataur A, Wang LY, Simon MC. N-terminal transactivaton domain confers target gene specificity of hypoxia inducible factors. Molecular Biology of the Cell, 2007 18:4528-4542.
5. 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.
6. Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2a promotes proliferation under hypoxia by enhancing c-Myc transcriptional activity. Cancer Cell 2007 11:335-347.
7. 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.