title: γ-H2AX promotes hepatocellular carcinoma angiogenesis via EGFR/HIF-1α/VEGF pathways under hypoxic condition.
abstract: 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.
authors.affiliation: 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.
authors.forename: Heng
authors.initials: H
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Rongliang
authors.initials: R
authors.lastname: Tong
authors.affiliation: 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.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lv
authors.affiliation: 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.
authors.forename: Chengli
authors.initials: C
authors.lastname: Du
authors.affiliation: 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.
authors.forename: Chuanhui
authors.initials: C
authors.lastname: Peng
authors.affiliation: 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.
authors.forename: Shaobing
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.affiliation: Key Lab of Combined Multi-Organ Transplantation, Ministry of Public Health, Hangzhou, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Jian
authors.initials: J
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism*; D016031:Liver Transplantation; D016513:Mice, SCID; D018613:Microscopy, Confocal; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D066246:ErbB Receptors