Abstract
BackgroundHepatocellular 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.Methods and resultsWe 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.ConclusionThis 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.
Highlights
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related death in human
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 reactive oxygen species (ROS) accumulation and NF-ĸB-dependent Vascular endothelial growth factor (VEGF) and Monocyte chemotactic protein-1 (MCP-1) up-regulation
No statistical differences were found in the age, hepatitis B virus (HBV) infection, presence of cirrhosis, liver function (Child grade), tumor size, or number of tumors between the alcoholic and nonalcoholic patients (P >0.05), except for gender (P =0.026; Table 1)
Summary
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. It is still unclear whether and how alcohol enhances the progression and metastasis of existing HCC. It is well recognized that both genetic and environmental factors contribute to human HCC. An important environmental factor, was classified as a group I carcinogen and chronic alcohol consumption has been recognized as an important risk factor for liver cancers [3,4]. Vascular endothelial growth factor (VEGF) is an essential player in tumor angiogenesis and mediates tumor aggressiveness [7,8,9]. Monocyte chemotactic protein-1 (MCP-1), a key CC chemokine responsible for trafficking and activation of monocytes/macrophages has been
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