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Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors

Mortality from liver cancer in humans is increasingly attributable to heavy or long-term alcohol consumption. The mechanisms by which alcohol exerts its carcinogenic effect are not well understood. In this study, the role of alcohol-induced endoplasmic reticulum (ER) stress response in liver cancer...

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Autores principales: Han, Hui, Hu, Jay, Lau, Mo Y., Feng, Min, Petrovic, Lydia M., Ji, Cheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813967/
https://www.ncbi.nlm.nih.gov/pubmed/24198826
http://dx.doi.org/10.3389/fgene.2013.00224
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author Han, Hui
Hu, Jay
Lau, Mo Y.
Feng, Min
Petrovic, Lydia M.
Ji, Cheng
author_facet Han, Hui
Hu, Jay
Lau, Mo Y.
Feng, Min
Petrovic, Lydia M.
Ji, Cheng
author_sort Han, Hui
collection PubMed
description Mortality from liver cancer in humans is increasingly attributable to heavy or long-term alcohol consumption. The mechanisms by which alcohol exerts its carcinogenic effect are not well understood. In this study, the role of alcohol-induced endoplasmic reticulum (ER) stress response in liver cancer development was investigated using an animal model with a liver knockout (KO) of the chaperone BiP and under constitutive hepatic ER stress. Long-term alcohol and high fat diet feeding resulted in higher levels of serum alanine aminotransferase, impaired ER stress response, and higher incidence of liver tumor in older (aged 16 months) KO females than in either middle-aged (6 months) KOs or older (aged 16 months) wild type females. In the older KO females, stronger effects of the alcohol on methylation of CpG islands at promoter regions of genes involved in the ER-associated degradation (ERAD) were also detected. Altered expression of ERAD factors including derlin 3, Creld2 (cysteine-rich with epidermal growth factor-like domains 2), Herpud1 (homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member), Wfs1 (Wolfram syndrome gene), and Yod1 (deubiquitinating enzyme 1) was co-present with decreased proteasome activities, increased estrogen receptor α variant (ERα36), and enhanced phosphorylations of ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) and STAT3 (the signal transducers and activators of transcription) in the older KO female fed alcohol. Our results suggest that long-term alcohol consumption and aging may promote liver tumorigenesis in females through interfering with DNA methylation and expression of genes involved in the ERAD.
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spelling pubmed-38139672013-11-06 Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors Han, Hui Hu, Jay Lau, Mo Y. Feng, Min Petrovic, Lydia M. Ji, Cheng Front Genet Endocrinology Mortality from liver cancer in humans is increasingly attributable to heavy or long-term alcohol consumption. The mechanisms by which alcohol exerts its carcinogenic effect are not well understood. In this study, the role of alcohol-induced endoplasmic reticulum (ER) stress response in liver cancer development was investigated using an animal model with a liver knockout (KO) of the chaperone BiP and under constitutive hepatic ER stress. Long-term alcohol and high fat diet feeding resulted in higher levels of serum alanine aminotransferase, impaired ER stress response, and higher incidence of liver tumor in older (aged 16 months) KO females than in either middle-aged (6 months) KOs or older (aged 16 months) wild type females. In the older KO females, stronger effects of the alcohol on methylation of CpG islands at promoter regions of genes involved in the ER-associated degradation (ERAD) were also detected. Altered expression of ERAD factors including derlin 3, Creld2 (cysteine-rich with epidermal growth factor-like domains 2), Herpud1 (homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member), Wfs1 (Wolfram syndrome gene), and Yod1 (deubiquitinating enzyme 1) was co-present with decreased proteasome activities, increased estrogen receptor α variant (ERα36), and enhanced phosphorylations of ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) and STAT3 (the signal transducers and activators of transcription) in the older KO female fed alcohol. Our results suggest that long-term alcohol consumption and aging may promote liver tumorigenesis in females through interfering with DNA methylation and expression of genes involved in the ERAD. Frontiers Media S.A. 2013-10-31 /pmc/articles/PMC3813967/ /pubmed/24198826 http://dx.doi.org/10.3389/fgene.2013.00224 Text en Copyright © 2013 Han, Hu, Lau, Feng, Petrovic and Ji. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Han, Hui
Hu, Jay
Lau, Mo Y.
Feng, Min
Petrovic, Lydia M.
Ji, Cheng
Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors
title Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors
title_full Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors
title_fullStr Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors
title_full_unstemmed Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors
title_short Altered methylation and expression of ER-associated degradation factors in long-term alcohol and constitutive ER stress-induced murine hepatic tumors
title_sort altered methylation and expression of er-associated degradation factors in long-term alcohol and constitutive er stress-induced murine hepatic tumors
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813967/
https://www.ncbi.nlm.nih.gov/pubmed/24198826
http://dx.doi.org/10.3389/fgene.2013.00224
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