Xiao Heng, Tong Rongliang, Ding Chaofeng, Lv Zhen, Du Chengli, Peng Chuanhui, Cheng Shaobing, Xie Haiyang, Zhou Lin, Wu Jian, Zheng Shusen
Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.
Oncotarget. 2015 Feb 10;6(4):2180-92. doi: 10.18632/oncotarget.2942.
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.
肝细胞癌（HCC）是最致命的癌症之一。通过mRNA微阵列分析，我们发现缺氧条件下H2AX表达降低。缺氧是诱导H2AX磷酸化（γ-H2AX）的重要生理和病理应激，但在HCC进展过程中γ-H2AX的调控机制仍不清楚。我们在此报告，HCC中γ-H2AX表达增加与肿瘤大小、血管侵犯、TNM分期以及肝移植（LT）后生存率降低相关。γ-H2AX基因敲低能够在体外有效抑制VEGF表达，并在体内抑制HCC的致瘤性和血管生成。在缺氧条件下，γ-H2AX对HCC血管生成活性的作用机制可能通过EGFR/HIF-1α/VEGF途径。联合检测γ-H2AX、HIF-1α和EGFR对LT后HCC具有更好的预后价值。本研究表明，γ-H2AX与HCC血管生成相关，γ-H2AX或γ-H2AX/EGFR/HIF-1α联合检测是LT后HCC预后的新型标志物及潜在治疗靶点。
