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Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis.

Publication ,  Journal Article
Chan, IS; Guy, CD; Machado, MV; Wank, A; Kadiyala, V; Michelotti, G; Choi, S; Swiderska-Syn, M; Karaca, G; Pereira, TA; Yip-Schneider, MT ...
Published in: Alcohol Clin Exp Res
March 2014

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.

Duke Scholars

Published In

Alcohol Clin Exp Res

DOI

EISSN

1530-0277

Publication Date

March 2014

Volume

38

Issue

3

Start / End Page

787 / 800

Location

England

Related Subject Headings

  • Substance Abuse
  • Rats
  • Random Allocation
  • Liver Neoplasms, Experimental
  • Liver
  • Hedgehog Proteins
  • Ethanol
  • Epithelial-Mesenchymal Transition
  • Central Nervous System Depressants
  • Carcinogenesis
 

Citation

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MLA
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Chan, I. S., Guy, C. D., Machado, M. V., Wank, A., Kadiyala, V., Michelotti, G., … Diehl, A. M. (2014). Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis. Alcohol Clin Exp Res, 38(3), 787–800. https://doi.org/10.1111/acer.12279
Chan, Isaac S., Cynthia D. Guy, Mariana V. Machado, Abigail Wank, Vishnu Kadiyala, Gregory Michelotti, Steve Choi, et al. “Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis.Alcohol Clin Exp Res 38, no. 3 (March 2014): 787–800. https://doi.org/10.1111/acer.12279.
Chan IS, Guy CD, Machado MV, Wank A, Kadiyala V, Michelotti G, et al. Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis. Alcohol Clin Exp Res. 2014 Mar;38(3):787–800.
Chan, Isaac S., et al. “Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis.Alcohol Clin Exp Res, vol. 38, no. 3, Mar. 2014, pp. 787–800. Pubmed, doi:10.1111/acer.12279.
Chan IS, Guy CD, Machado MV, Wank A, Kadiyala V, Michelotti G, Choi S, Swiderska-Syn M, Karaca G, Pereira TA, Yip-Schneider MT, Max Schmidt C, Diehl AM. Alcohol activates the hedgehog pathway and induces related procarcinogenic processes in the alcohol-preferring rat model of hepatocarcinogenesis. Alcohol Clin Exp Res. 2014 Mar;38(3):787–800.
Journal cover image

Published In

Alcohol Clin Exp Res

DOI

EISSN

1530-0277

Publication Date

March 2014

Volume

38

Issue

3

Start / End Page

787 / 800

Location

England

Related Subject Headings

  • Substance Abuse
  • Rats
  • Random Allocation
  • Liver Neoplasms, Experimental
  • Liver
  • Hedgehog Proteins
  • Ethanol
  • Epithelial-Mesenchymal Transition
  • Central Nervous System Depressants
  • Carcinogenesis