The role of hypoxia inducible factor-1 in hepatocellular carcinoma

Abstract

Hypoxia is a common feature of many solid tumors, including hepatocellular carcinoma (HCC). Hypoxia can promote tumor progression and induce radiation and chemotherapy resistance. As one of the major mediators of hypoxic response, hypoxia inducible factor-1 (HIF-1) has been shown to activate hypoxia-responsive genes, which are involved in multiple aspects of tumorigenesis and cancer progression, including proliferation, metabolism, angiogenesis, invasion, metastasis and therapy resistance. It has been demonstrated that a high level of HIF-1 in the HCC microenvironment leads to enhanced proliferation and survival of HCC cells. Accordingly, overexpression, of HIF-1 is associated with poor prognosis in HCC. In this review, we described the mechanism by which HIF-1 is regulated and how HIF-1 mediates the biological effects of hypoxia in tissues. We also summarized the latest findings concerning the role of HIF-1 in the development of HCC, which could shed light on new therapeutic approaches for the treatment of HCC.

Figure 1

Domain structures of HIF-1α and their potential function in stability and transcriptional activity of HIF-1.

Figure 2

Oxygen-dependent regulation of HIF-1α activity. Under normoxic conditions, HIF-1α subunit is rapidly hydroxylated by prolyl hydroxylases (PHDs) and binds to von Hippel-Lindau protein (pVHL), resulting in the rapid ubiquitination of HIF-1α and subsequent proteasomeal degradation. Under hypoxic conditions, HIF-1α is stabilized and translocated into the nucleus by importin α/β and dimerizes with HIF-1β. The HIF heterodimer affects transcription of target genes by binding to a hypoxia response element (HRE) in the upstream promoter region after cooperation with transcriptional coactivators such as p300/CBP.