title: Hepatitis C virus and alcohol: same mitotic targets but different signaling pathways.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Our results support the idea that HCV and alcohol may promote oncogenesis by acting through the same mitotic proteins, but via different signaling pathways.
authors.affiliation: Laboratory of Molecular Virology and Oncology, Fondazione A. Cesalpino, University of Rome, Rome, V. le del Policlinico 155, 00161 Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Alisi
authors.forename: Monica
authors.initials: M
authors.lastname: Ghidinelli
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zerbini
authors.forename: Gabriele
authors.initials: G
authors.lastname: Missale
authors.forename: Clara
authors.initials: C
authors.lastname: Balsano
mesh_terms: D064096:Aurora Kinase A; D064127:Aurora Kinases; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002492:Central Nervous System Depressants / Q000378:metabolism / Q000494:pharmacology; D056744:Cyclin B1 / Q000378:metabolism; D004347:Drug Interactions; D004642:Emodin / Q000378:metabolism / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology; D056945:Hep G2 Cells; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D066298:In Vitro Techniques; D008108:Liver Diseases, Alcoholic / Q000150:complications / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014404:Tubulin / Q000378:metabolism
chemical_list: D002492:Central Nervous System Depressants; D056744:Cyclin B1; D047428:Protein Kinase Inhibitors; D014404:Tubulin; D000431:Ethanol; C576917:AURKA protein, human; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D004642:Emodin