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Hepatology International, 2013
Alcohol abuse and obesity are two known risk factors for hepatocellular carcinoma (HCC) that also... more Alcohol abuse and obesity are two known risk factors for hepatocellular carcinoma (HCC) that also synergistically promote HBV/HCV-related carcinogenesis. TLR4, the PAMP for endotoxin participates in inflammatory processes such as M1 activation of hepatic macrophages in alcoholic liver disease. However its role in liver carcinogenesis via ectopic expression and activation, has only recently been revealed in alcohol/HCV-associated HCC models. Alcohol feeding to mice expressing the HCV Ns5a in a hepatocyte specific manner, aggravates liver inflammation via activation of overexpressed TLR4 in the parenchymal cells. Long-term alcohol feeding produces liver tumors in these transgenic mice in a manner dependent on TLR4. From these mice, CD133+/ CD49f+ tumor initiating stem cell-like cells (TICs) have been isolated. These TICs exhibit selfrenewal and tumorigenic activities driven by TLR4-dependent upregulation of the stem cell factor NANOG. Defective TGF-β tumor suppressor pathway is identified in the TICs and mediated by NANOG target genes Igf2bp3 and Yap1. This TGF-β pathway antagonism is responsible in part for TIC's tumorigenic activity and chemoresistance. Conversely, mice with attenuated TGF-β pathway due to haploinsufficiency of β2-Spectrin, spontaneously develop liver tumors and alcoholfeeding increases tumor incidence in a TLR4 dependent manner. This reciprocal antagonism between TLR4 and TGF-β pathways may serve as a novel therapeutic target for HCC.
Alcoholism: Clinical and Experimental Research, 2010
Hepatitis C virus infection affects 170 million people worldwide and the majority of individuals ... more Hepatitis C virus infection affects 170 million people worldwide and the majority of individuals exposed to HCV develop chronic hepatitis leading to progressive liver damage, cirrhosis and hepatocellular cancer. The natural history of HCV infection is influenced by genetic and environmental factors of which chronic alcohol use is an independent risk factor for cirrhosis in HCV infected individuals. Both the hepatitis C virus and alcohol damage the liver and result in immune alterations contributing to both decreased viral clearance and liver injury. This review will capture the major components of the interactions between alcohol and HCV infection to provide better understanding for the molecular basis of the dangerous combination of alcohol use and HCV infection. Common targets of HCV and alcohol involve innate immune recognition and dendritic cells, the critical cell type in antigen presentation and antiviral immunity. In addition, both alcohol and HCV affect intracellular processes critical for hepatocyte and immune cell functions including mitochondrial and proteasomal activation. Finally, both chronic alcohol use and hepatitis C virus infection increase the risk of hepatocellular cancer. The common molecular mechanisms underlying the pathological interactions between alcohol and HCV include the modulation of cytokine production, lipopolysaccharide (LPS)-TLR4 signaling, and reactive oxygen species (ROS) production. LPS-induced chronic inflammation is not only a major cause of progressive liver injury and fibrosis but it can also contribute to modification of the tissue environment and stem cells to promote hepatocellular cancer development. Alteration of these # Corresponding authors:
The Journal of Immunology, 2010
Hepatology International, 2013
Alcohol abuse and obesity are two known risk factors for hepatocellular carcinoma (HCC) that also... more Alcohol abuse and obesity are two known risk factors for hepatocellular carcinoma (HCC) that also synergistically promote HBV/HCV-related carcinogenesis. TLR4, the PAMP for endotoxin participates in inflammatory processes such as M1 activation of hepatic macrophages in alcoholic liver disease. However its role in liver carcinogenesis via ectopic expression and activation, has only recently been revealed in alcohol/HCV-associated HCC models. Alcohol feeding to mice expressing the HCV Ns5a in a hepatocyte specific manner, aggravates liver inflammation via activation of overexpressed TLR4 in the parenchymal cells. Long-term alcohol feeding produces liver tumors in these transgenic mice in a manner dependent on TLR4. From these mice, CD133+/ CD49f+ tumor initiating stem cell-like cells (TICs) have been isolated. These TICs exhibit selfrenewal and tumorigenic activities driven by TLR4-dependent upregulation of the stem cell factor NANOG. Defective TGF-β tumor suppressor pathway is identified in the TICs and mediated by NANOG target genes Igf2bp3 and Yap1. This TGF-β pathway antagonism is responsible in part for TIC's tumorigenic activity and chemoresistance. Conversely, mice with attenuated TGF-β pathway due to haploinsufficiency of β2-Spectrin, spontaneously develop liver tumors and alcoholfeeding increases tumor incidence in a TLR4 dependent manner. This reciprocal antagonism between TLR4 and TGF-β pathways may serve as a novel therapeutic target for HCC.
Alcoholism: Clinical and Experimental Research, 2010
Hepatitis C virus infection affects 170 million people worldwide and the majority of individuals ... more Hepatitis C virus infection affects 170 million people worldwide and the majority of individuals exposed to HCV develop chronic hepatitis leading to progressive liver damage, cirrhosis and hepatocellular cancer. The natural history of HCV infection is influenced by genetic and environmental factors of which chronic alcohol use is an independent risk factor for cirrhosis in HCV infected individuals. Both the hepatitis C virus and alcohol damage the liver and result in immune alterations contributing to both decreased viral clearance and liver injury. This review will capture the major components of the interactions between alcohol and HCV infection to provide better understanding for the molecular basis of the dangerous combination of alcohol use and HCV infection. Common targets of HCV and alcohol involve innate immune recognition and dendritic cells, the critical cell type in antigen presentation and antiviral immunity. In addition, both alcohol and HCV affect intracellular processes critical for hepatocyte and immune cell functions including mitochondrial and proteasomal activation. Finally, both chronic alcohol use and hepatitis C virus infection increase the risk of hepatocellular cancer. The common molecular mechanisms underlying the pathological interactions between alcohol and HCV include the modulation of cytokine production, lipopolysaccharide (LPS)-TLR4 signaling, and reactive oxygen species (ROS) production. LPS-induced chronic inflammation is not only a major cause of progressive liver injury and fibrosis but it can also contribute to modification of the tissue environment and stem cells to promote hepatocellular cancer development. Alteration of these # Corresponding authors:
The Journal of Immunology, 2010