Hypoxia inducible factors in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma is one of the most prevalent and lethal cancers with limited therapeutic options. Pathogenesis of this disease involves tumor hypoxia and the activation of hypoxia inducible factors. In this review, we describe the current understanding of hypoxia signaling pathway and summarize the expression, function and target genes of hypoxia inducible factors in hepatocellular carcinoma. We also highlight the recent progress in hypoxia-targeted therapeutic strategies in hepatocellular carcinoma and discuss further the future efforts for the study of hypoxia and/or hypoxia inducible factors in this deadly disease.

Keywords: HIF; hepatoma; hypoxia; liver cancer; therapy.

Figure 1. Regulation of hypoxia pathway

HIF1α and HIF1β are used as examples. At post-transcriptional level, HIF1α mRNA is repressed by miR-199a-5p, miR-338-3p, miR-93 and miR-122. Under normoxia, HIF1α protein is hydroxylated at P402 and P564 by PHDs and subsequently degraded by pVHL through the Ubiquitin–Proteasome Pathway. Additionally, asparaginyl hydroxylation of HIF1α by FIH-1 at N806 impairs its interaction with CBP/P300. Hypoxia blocks the hydroxylation and proteasomal degradation of HIF1α, leading to its stabilization and nuclear translocation. Within nucleus, HIF1α forms heterodimer with HIF1β, and activate the expression of hypoxia responsive genes with the help from additional transcriptional co-factors, such as CBP/P300, Pol2, CDK8, and TIP60.

Figure 2. Involvement of HIFs and their targets in cancer hallmarks (modified from the original figure from Hanahan and Weinberg [113])

The function of HIFs has been implicated in promoting angiogenesis, invasion/metastasis, proliferation, glycolysis, therapeutic resistance, inflammation, and immune evasion.