title: Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related death in human. Alcohol is a known risk factor for HCC. However it is still unclear whether and how alcohol enhances the progression and metastasis of existing HCC.
  
  
  RESULTS
  We first retrospectively investigated 52 HCC patients (24 alcohol-drinkers and 28 non-drinkers), and found a positive correlation between alcohol consumption and advanced Tumor-Node-Metastasis (TNM) stages, higher vessel invasion and poorer prognosis. In vitro and in vivo experiments further indicated that alcohol promoted the progression and migration/invasion of HCC. Specifically, in a 3-D tumor/endothelial co-culture system, we found that alcohol enhanced the migration/invasion of HepG2 cells and increased tumor angiogenesis. Consistently, higher expression of VEGF, MCP-1 and NF-κB was observed in HCC tissues of alcohol-drinkers. Alcohol induced the accumulation of intracellular reactive oxygen species (ROS) and the activation of NF-κB signaling in HepG2 cells. Conversely, blockage of alcohol-mediated ROS accumulation and NF-κB signaling inhibited alcohol-induced expression of VEGF and MCP-1, the tumor growth, angiogenesis and metastasis.
  
  
  CONCLUSIONS
  This study suggested that chronic moderate alcohol consumption may promote the progression and metastasis of HCC; the oncogenic effect may be at least partially mediated by the ROS accumulation and NF-ĸB-dependent VEGF and MCP-1 up-regulation.
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 1035934043@qq.com.|Department of Burns, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, P.R. China. 1035934043@qq.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. y214365879@qq.com.
authors.forename: Jin-Lian
authors.initials: JL
authors.lastname: Yang
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 919835078@qq.com.
authors.forename: Ke-ke
authors.initials: KK
authors.lastname: Yu
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 414235163@qq.com.|Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, 40536, USA. 414235163@qq.com.
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. youzhixu08@gmail.com.
authors.forename: You-zhi
authors.initials: YZ
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 644713824@qq.com.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 2322969581@qq.com.
authors.forename: Yan-min
authors.initials: YM
authors.lastname: Lu
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 2254468@qq.com.
authors.forename: Hao-shu
authors.initials: HS
authors.lastname: Fang
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 409416935@qq.com.|Department of Clinical Medicine, Anhui Medical University, Hefei, Anhui, 230032, P.R. China. 409416935@qq.com.
authors.forename: Xin-yi
authors.initials: XY
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 578743851@qq.com.
authors.forename: Zhong-qian
authors.initials: ZQ
authors.lastname: Hu
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 13965021937@163.com.
authors.forename: Fei-fei
authors.initials: FF
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. 2816393992@qq.com.
authors.forename: Lixin
authors.initials: L
authors.lastname: Kan
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. Jialuo888@uky.edu.|Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, 40536, USA. Jialuo888@uky.edu.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, 81 MeiShan Road, Hefei, Anhui, 230032, P.R. China. sywang@ahmu.edu.cn.
authors.forename: Si-Ying
authors.initials: SY
authors.lastname: Wang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D018932:Chemokine CCL2 / Q000235:genetics; D018450:Disease Progression; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics*; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016328:NF-kappa B; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000431:Ethanol