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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:

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 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.