Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma

Fei Wang; Jin-Lian Yang; Ke-ke Yu; Mei Xu; You-zhi Xu; Li Chen; Yan-min Lu; Hao-shu Fang; Xin-yi Wang; Zhong-qian Hu; Fei-fei Li; Lixin Kan; Jia Luo; Si-Ying Wang

doi:10.1186/s12943-014-0274-0

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Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma

Journal article

Open access

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Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma

Fei Wang, Jin-Lian Yang, Ke-ke Yu, Mei Xu, You-zhi Xu, Li Chen, Yan-min Lu, Hao-shu Fang, Xin-yi Wang, Zhong-qian Hu, …

Molecular cancer, Vol.14(1), pp.10-14

01/27/2015

DOI: 10.1186/s12943-014-0274-0

PMCID: PMC4320626

PMID: 25622857

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Abstract

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. 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. 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.

Animals

Carcinoma, Hepatocellular - genetics

Carcinoma, Hepatocellular - pathology

Cell Line, Tumor

Cell Movement - genetics

Chemokine CCL2 - genetics

Disease Progression

Ethanol - adverse effects

Female

Hep G2 Cells

Humans

Liver Neoplasms - genetics

Liver Neoplasms - pathology

Male

Mice

Mice, Nude

Middle Aged

Neoplasm Invasiveness - genetics

Neovascularization, Pathologic - genetics

Neovascularization, Pathologic - pathology

NF-kappa B - genetics

NIH 3T3 Cells

Retrospective Studies

Signal Transduction - genetics

Vascular Endothelial Growth Factor A - genetics

Details

Title: Subtitle: Activation of the NF-κB pathway as a mechanism of alcohol enhanced progression and metastasis of human hepatocellular carcinoma
Creators: Fei Wang - Anhui Medical University
Jin-Lian Yang - Anhui Medical University
Ke-ke Yu - Anhui Medical University
Mei Xu - Anhui Medical University
You-zhi Xu - Anhui Medical University
Li Chen - Anhui Medical University
Yan-min Lu - Anhui Medical University
Hao-shu Fang - Anhui Medical University
Xin-yi Wang - Anhui Medical University
Zhong-qian Hu - Anhui Medical University
Fei-fei Li - Anhui Medical University
Lixin Kan - Anhui Medical University
Jia Luo - University of Kentucky
Si-Ying Wang - Anhui Medical University
Resource Type: Journal article
Publication Details: Molecular cancer, Vol.14(1), pp.10-14
DOI: 10.1186/s12943-014-0274-0
PMID: 25622857
PMCID: PMC4320626
NLM abbreviation: Mol Cancer
ISSN: 1476-4598
eISSN: 1476-4598
Grant note: AA015407 / NIAAA NIH HHS AA017226 / NIAAA NIH HHS R01 AA015407 / NIAAA NIH HHS R01 AA017226 / NIAAA NIH HHS
Language: English
Date published: 01/27/2015
Academic Unit: Pathology
Record Identifier: 9984201251702771

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