Chronic Ethanol Feeding Accelerates Hepatocellular Carcinoma Progression in a Sex‐Dependent Manner in a Mouse Model of Hepatocarcinogenesis

Brandon-Warner, Elizabeth; Walling, Tracy L.; Schrum, Laura W.; McKillop, Iain H.

doi:10.1111/j.1530-0277.2011.01660.x

Cited by 77 publications

(89 citation statements)

References 45 publications

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“…Introduction and maintenance on EtOH-DW with the CD regimen resulted in reduced tumor formation (44%) and no significant difference for those on a HFD. This is in contrast to previous results from our group utilizing the same EtOH-DW regimen in B6C3F1 mice, supporting inter-strain differences in susceptibility to hepatic tumor formation and progression, despite similar blood alcohol content levels (12–15 mM/L) in the two strains (Brandon-Warneret al, 2012b; Thompson et al, 2013). …”

Section: Microrna Profiling To Identify Promoters Of Hcc Progresssupporting

confidence: 46%

Alcoholic and non-alcoholic steatohepatitis

Neuman

French

et al. 2014

Experimental and Molecular Pathology

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This paper is based upon the “Charles Lieber Satellite Symposia” organized by Manuela G. Neuman at the Research Society on Alcoholism (RSA) Annual Meetings, 2013 and 2014. The present review includes pre-clinical, translational and clinical research that characterize alcoholic liver disease (ALD) and non-alcoholic steatohepatitis (NASH). In addition, a literature search in the discussed area was performed. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD. The liver biopsy can confirm the etiology of NASH or alcoholic steatohepatitis (ASH) and assess structural alterations of cells, their organelles, as well as inflammatory activity. Three histological stages of ALD are simple steatosis, ASH, and chronic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes such as cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Alcohol mediated hepatocarcinogenesis, immune response to alcohol in ASH, as well as the role of other risk factors such as its comorbidities with chronic viral hepatitis in the presence or absence of human deficiency virus are discussed. Dysregulation of hepatic methylation, as result of ethanol exposure, in hepatocytes transfected with hepatitis C virus (HCV), illustrates an impaired interferon signaling. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota are suggested. The clinical aspects of NASH, as part of metabolic syndrome in the aging population, are offered. The integrative symposia investigate different aspects of alcohol-induced liver damage and possible repair. We aim to (1) determine the immuno-pathology of alcohol-induced liver damage, (2) examine the role of genetics in the development of ASH, (3) propose diagnostic markers of ASH and NASH, (4) examine age differences, (5) develop common research tools to study alcohol-induced effects in clinical and pre-clinical studies, and (6) focus on factors that aggravate severity of organ-damage. The intention of these symposia is to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

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Section: Microrna Profiling To Identify Promoters Of Hcc Progresssupporting

confidence: 46%

Alcoholic and non-alcoholic steatohepatitis

Neuman

French

et al. 2014

Experimental and Molecular Pathology

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“…Tumor initiation results from ethanol (EtOH) metabolism by alcohol dehydrogenase and cytochrome P450 (CYP) 2E1 thus, producing acetaldehyde and reactive oxygen species which interfere with DNA synthesis and repair mechanisms, leading to mutagenicity and tumorigenesis (4, 11). In addition to initiating effects, EtOH also has proliferative and tumor promoting effects in the liver (7, 8, 12). Our laboratory has demonstrated that EtOH stimulates hepatocyte proliferation in rodents in association with liver injury and hepatic vitamin A depletion (13-15).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, we hypothesized that dietary intervention with soy may prevent EtOH-mediated tumor promoting effects by inhibiting β-catenin signaling and associated proliferation mechanisms. To test this hypothesis, we utilized a two-stage mouse model in which tumor initiation by a genotoxic compound, diethylnitrosamine (DEN), was followed by the promoting agent, an EtOH liquid diet (13,16, 29), containing either casein or soy protein isolate (SPI) as the sole source protein source. Administration of these diets continued for 16 wks, at which livers were analyzed for the presence of adenomas.…”

Section: Introductionmentioning

confidence: 99%

Soy Protein Isolate Protects Against Ethanol-Mediated Tumor Progression in Diethylnitrosamine-Treated Male Mice

Mercer

Pulliam

Hennings

et al. 2016

Cancer Prevention Research

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In this study, diethylnitrosamine-treated male mice were assigned to 3 groups: a 35% high fat ethanol liquid diet (EtOH) with casein as the protein source, the same EtOH liquid diet with soy protein isolate as the sole protein source (EtOH/SPI) and a chow group. EtOH feeding continued for 16 wks. As expected, EtOH increased the incidence and multiplicity of basophilic lesions and adenomas compared to the chow group, p<0.05. Soy protein replacement of casein in the EtOH diet significantly reduced adenoma progression when compared to the EtOH and EtOH/SPI group, p<0.05. Tumor reduction in the EtOH/SPI group corresponded to reduced liver injury associated with decreased hepatic tumor necrosis factor α (Tnfα) and Cd14 antigen (Cd14) expression and decreased nuclear accumulation of NFκB1 protein compared to the EtOH group (p<0.05). Detection of sphingolipids using high resolution MALDI-FTICR Imaging mass spectrometry revealed increased accumulation of long acyl chain ceramide species, and sphingosine-1-phosphate (S1P) in the EtOH group that were significantly reduced in the EtOH/SPI group. Chronic EtOH feeding also increased mRNA expression of β-catenin transcriptional targets, including cyclin D1 (Ccnd1), matrix metallopeptidase 7 (Mmp7) and glutamine synthetase (Glns), which were reduced in the EtOH/SPI group, p<0.05. We conclude that soy prevents tumorigenesis by reducing pro-inflammatory and oxidative environment resulting from EtOH-induced hepatic injury, and by reducing hepatocyte proliferation through inhibition of β-catenin signaling. These mechanisms may involve changes in sphingolipid signaling.

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“…This stage is characterized by release of TGF-β1, mostly by Kupffer cells 4 , and activation of Hepatic stellate cells (HSCs) 13,14 . Furthermore, a recent study has demonstrated that addition of ethanol to drinking water increased tumor incidence in DEN-injected male mice 15 , suggesting that this model can be used to study the effects of ethanol on HCC progression.…”

Section: Ald Progression In Patientsmentioning

confidence: 99%

The Role of IL-17 Signaling in Regulation of the Liver–Brain Axis and Intestinal Permeability in Alcoholic Liver Disease

Liu

et al. 2016

Curr Pathobiol Rep

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Alcoholic liver disease (ALD) progresses from a normal liver, to steatosis, steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Despite intensive studies, the pathogenesis of ALD is poorly understood, in part due to a lack of suitable animal models which mimic the stages of ALD progression. Furthermore, the role of IL-17 in ALD has not been evaluated. We and others have recently demonstrated that IL-17 signaling plays a critical role in development of liver fibrosis and cancer. Here we summarize the most recent evidence supporting the role of IL-17 in ALD. As a result of a collaborative effort of Drs. Karin, Gao, Tsukamoto and Kisseleva, we developed several improved models of ALD in mice: 1) chronic-plus-binge model that mimics early stages of steatohepatitis, 2) intragastric ethanol feeding model that mimics alcoholic steatohepatitis and fibrosis, and 3) diethylnitrosamine (DEN)+alcohol model that mimics alcoholic liver cancer. These models might provide new insights into the mechanism of IL-17 signaling in ALD and help identify novel therapeutic targets.

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Chronic Ethanol Feeding Accelerates Hepatocellular Carcinoma Progression in a Sex‐Dependent Manner in a Mouse Model of Hepatocarcinogenesis

Cited by 77 publications

References 45 publications

Alcoholic and non-alcoholic steatohepatitis

Alcoholic and non-alcoholic steatohepatitis

Soy Protein Isolate Protects Against Ethanol-Mediated Tumor Progression in Diethylnitrosamine-Treated Male Mice

The Role of IL-17 Signaling in Regulation of the Liver–Brain Axis and Intestinal Permeability in Alcoholic Liver Disease

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