Hepatitis C virus and alcohol: Same mitotic targets but different signaling pathways

• Published in: Journal of hepatology Vol. 54; no. 5; pp. 956 - 963
• Main Authors: Alisi, Anna, Ghidinelli, Monica, Zerbini, Alessandro, Missale, Gabriele, Balsano, Clara
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.05.2011; Elsevier
• Subjects: Aurora Kinase A; Aurora Kinases; Biological and medical sciences; Biopsy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - virology; Central Nervous System Depressants - metabolism; Central Nervous System Depressants - pharmacology; Cyclin B1; Cyclin B1 - metabolism; Drug Interactions; Emodin - metabolism; Emodin - pharmacology; Ethanol; Ethanol - metabolism; Ethanol - pharmacology; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; HCC; HCV; Hep G2 Cells; Hepatitis C, Chronic - metabolism; Hepatitis C, Chronic - pathology; Humans; In Vitro Techniques; Liver Diseases, Alcoholic - complications; Liver Diseases, Alcoholic - metabolism; Liver Diseases, Alcoholic - pathology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - virology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Mitosis - physiology; Phosphorylation - physiology; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - metabolism; Signal Transduction - physiology; Tubulin - metabolism; Tumors; Ethanol; JNK; NF-kB; HCC; HCCs; siRNA; NASH; Cyclin B1; FAK; PI3K; PKR; HCV; HBV; Aurora kinase A; p38MAPK; nuclear factor-kB; hepatitis B virus; hepatocellular carcinomas; hepatitis C virus; small interference RNA; RNA-activated protein kinase; c-Jun N-terminal kinase; focal adhesion kinase; p38 mitogen-activated protein kinase; phosphatydil-inositol-3 kinase; non-alcoholic steatohepatitis; Enzyme; Transferases; Cyclin; Hepatic disease; Alcohol; Hepatocellular carcinoma; Malignant tumor; Cyclin B1: Ethanol; Virus; Kinase; Gastroenterology; Digestive diseases; Flaviviridae; Hepatitis C virus; Hepacivirus; Cancer
• DOI: 10.1016/j.jhep.2010.08.016
• ISSN: 0168-8278; 1600-0641

Chromosomal aberrations are frequently observed in hepatitis C virus (HCV)- and alcohol-related hepatocellular carcinomas (HCCs). The mechanisms by which chromosomal aberrations occur during hepatocarcinogenesis are still unknown. However, these aberrations are considered to be the result of deregulation of some mitotic proteins, including the alteration of Cyclin B1 and Aurora kinase A expression, and the phosphorylation of gamma-tubulin. Our study aims at investigating changes in expression of the above mentioned proteins and related intracellular pathways, in in vitro and in vivo models of both HCV- and alcohol- dependent HCCs. In this study, the molecular defects and the mechanisms involved in deregulation of the mitotic machinery were analyzed in human hepatoma cells, expressing HCV proteins treated or not with ethanol, and in liver tissues from control subjects (n=10) and patients with HCV- (n=10) or alcohol-related (n=10) HCCs. Expression of Cyclin B1, Aurora kinase A, and tyrosine-phosphorylated gamma-tubulin was analyzed in models reproducing HCV infection and ethanol treatment in HCC cells. Interestingly, HCV and alcohol increased the expression of Cyclin B, Aurora kinase A, and tyrosine-phosphorylated gamma-tubulin also in tissues from patients with HCV- or alcohol-related HCCs. In vitro models suggest that HCV requires the expression of PKR (RNA-activated protein kinase), as well as JNK (c-Jun N-terminal kinase) and p38MAPK (p38 mitogen-activated protein kinase) proteins; while, ethanol bypasses all these pathways. Our results support the idea that HCV and alcohol may promote oncogenesis by acting through the same mitotic proteins, but via different signaling pathways.