γ-H2AX promotes hepatocellular carcinoma angiogenesis via EGFR/HIF-1α/VEGF pathways under hypoxic condition

Hepatocellular carcinoma (HCC) is one of the most deadly cancers. Using mRNA microarray analysis, we found that H2AX decreased under hypoxic conditions. Hypoxia is an important physiological and pathological stress that induces H2AX phosphorylation (gamma-H2AX), but the regulatory mechanism of gamma-H2AX remains elusive in the progress of HCC. We report here that increased gamma-H2AX expression in HCC is associated with tumor size, vascular invasion, TNM stage and reduced survival rate after liver transplantation (LT). gamma-H2AX knockdown was able to effectively inhibit VEGF expression in vitro and tumorigenicity and angiogenesis of HCC in vivo. The mechanism of gamma-H2AX on the angiogenic activity of HCC might go through EGFR/HIF-1 alpha/VEGF pathways under hypoxic conditions. Combined gamma-H2AX, HIF-1 alpha and EGFR has better prognostic value for HCC after LT. This study suggests that gamma-H2AX is associated with angiogenesis of HCC and gamma-H2AX or a combination of gamma-H2AX/EGFR/HIF-1 alpha is a novel marker in the prognosis of HCC after LT and a potential therapeutic target.