γ-H2AX promotes hepatocellular carcinoma angiogenesis via EGFR/HIF-1α/VEGF pathways under hypoxic condition
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Heng Xiao1,2,*, Rongliang Tong1,2,*, Chaofeng Ding1,2, Zhen Lv1,2, Chengli Du1,2, Chuanhui Peng1,2, Shaobing Cheng1,2, Haiyang Xie2, Lin Zhou2, Jian Wu1,2 and Shusen Zheng1,2
1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
2 Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China
* These authors contributed equally to this work
Jian Wu, email:
Shusen Zheng, email:
Keywords: hepatocellular carcinoma (HCC), γ-H2AX, angiogenesis, vascular endothelial growth factor (VEGF), epidermal growth factor receptor(EGFR), hypoxia inducible factor 1α (HIF-1α)
Received: August 23, 2014 Accepted: December 09, 2014 Published: December 10, 2014
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 (γ-H2AX), but the regulatory mechanism of γ-H2AX remains elusive in the progress of HCC. We report here that increased γ-H2AX expression in HCC is associated with tumor size, vascular invasion, TNM stage and reduced survival rate after liver transplantation (LT). γ-H2AX knockdown was able to effectively inhibit VEGF expression in vitro and tumorigenicity and angiogenesis of HCC in vivo. The mechanism of γ-H2AX on the angiogenic activity of HCC might go through EGFR/HIF-1α/VEGF pathways under hypoxic conditions. Combined γ-H2AX, HIF-1α and EGFR has better prognostic value for HCC after LT. This study suggests that γ-H2AX is associated with angiogenesis of HCC and γ-H2AX or a combination of γ-H2AX/EGFR/HIF-1α is a novel marker in the prognosis of HCC after LT and a potential therapeutic target.
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