title: Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis.
abstract: BACKGROUND
  Alcohol consumption promotes hepatocellular carcinoma (HCC). The responsible mechanisms are not well understood. Hepatocarcinogenesis increases with age and is enhanced by factors that impose a demand for liver regeneration. Because alcohol is hepatotoxic, habitual alcohol ingestion evokes a recurrent demand for hepatic regeneration. The alcohol-preferring (P) rat model mimics the level of alcohol consumption by humans who habitually abuse alcohol. Previously, we showed that habitual heavy alcohol ingestion amplified age-related hepatocarcinogenesis in P rats, with over 80% of alcohol-consuming P rats developing HCCs after 18 months of alcohol exposure, compared with only 5% of water-drinking controls.
  
  
  METHODS
  Herein, we used quantitative real-time PCR and quantitative immunocytochemistry to compare liver tissues from alcohol-consuming P rats and water-fed P rat controls after 6, 12, or 18 months of drinking. We aimed to identify potential mechanisms that might underlie the differences in liver cancer formation and hypothesized that chronic alcohol ingestion would activate Hedgehog (HH), a regenerative signaling pathway that is overactivated in HCC.
  
  
  RESULTS
  Chronic alcohol ingestion amplified age-related degenerative changes in hepatocytes, but did not cause appreciable liver inflammation or fibrosis even after 18 months of heavy drinking. HH signaling was also enhanced by alcohol exposure, as evidenced by increased levels of mRNAs encoding HH ligands, HH-regulated transcription factors, and HH target genes. Immunocytochemistry confirmed increased alcohol-related accumulation of HH ligand-producing cells and HH-responsive target cells. HH-related regenerative responses were also induced in alcohol-exposed rats. Three of these processes (i.e., deregulated progenitor expansion, the reverse Warburg effect, and epithelial-to-mesenchymal transitions) are known to promote cancer growth in other tissues.
  
  
  CONCLUSIONS
  Alcohol-related changes in Hedgehog signaling and resultant deregulation of liver cell replacement might promote hepatocarcinogenesis.
authors.affiliation: Department of Medicine , Duke University, Durham, North Carolina; Department of Genetics , The University of North Carolina School of Medicine, Chapel Hill, North Carolina.
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Chan
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Guy
authors.forename: Mariana V
authors.initials: MV
authors.lastname: Machado
authors.forename: Abigail
authors.initials: A
authors.lastname: Wank
authors.forename: Vishnu
authors.initials: V
authors.lastname: Kadiyala
authors.forename: Gregory
authors.initials: G
authors.lastname: Michelotti
authors.forename: Steve
authors.initials: S
authors.lastname: Choi
authors.forename: Marzena
authors.initials: M
authors.lastname: Swiderska-Syn
authors.forename: Gamze
authors.initials: G
authors.lastname: Karaca
authors.forename: Thiago A
authors.initials: TA
authors.lastname: Pereira
authors.forename: Michele T
authors.initials: MT
authors.lastname: Yip-Schneider
authors.forename: C
authors.initials: C
authors.lastname: Max Schmidt
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000009:adverse effects*; D058750:Epithelial-Mesenchymal Transition; D000431:Ethanol / Q000009:adverse effects*; D053823:Hedgehog Proteins / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D011897:Random Allocation; D051381:Rats
chemical_list: D002492:Central Nervous System Depressants; D053823:Hedgehog Proteins; D000431:Ethanol
keywords: Epithelial-to-Mesenchymal Transitions; Hedgehog; Liver Cancer; Liver Progenitors; Reverse Warburg Effect