Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis in Male Mice through Activation of the Wnt/β-Catenin Signaling Pathway

Mercer, Kelly E.; Hennings, Leah; Sharma, Neha; Lai, Keith; Cleves, Mario A.; Wynne, Rebecca; Badger, Thomas M.; Ronis, Martin J. J.

doi:10.1158/1940-6207.capr-13-0444-t

Cited by 45 publications

(74 citation statements)

References 54 publications

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“…For scoring of necrosis, the presence of necrotic foci was assessed using a scale where 0 ϭ none, 1 ϭ few, and 2 ϭ many. Fibrosis was detected histologically by picrosirius red staining of collagen (20). Inflammatory cell populations were also assessed by immunohistochemical staining using F4/80 as a marker of macrophages and CD3 as a marker of thymus-derived intrahepatic T cells.…”

Section: Methodsmentioning

confidence: 99%

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Increased 4-hydroxynonenal protein adducts in male GSTA4–4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease

Ronis

Mercer

Gannon

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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To test the significance of lipid peroxidation in the development of alcoholic liver injury, an ethanol (EtOH) liquid diet was fed to male 129/SvJ mice (wild-type, WT) and glutathione S-transferase A4–4-null (GSTA4−/−) mice for 40 days. GSTA4−/− mice were crossed with peroxisome proliferator-activated receptor-α-null mice (PPAR-α−/−), and the effects of EtOH in the resulting double knockout (dKO) mice were compared with the other strains. EtOH increased lipid peroxidation in all except WT mice ( P < 0.05). Increased steatosis and mRNA expression of the inflammatory markers CXCL2, tumor necrosis factor-α (TNF-α), and α-smooth muscle actin (α-SMA) were observed in EtOH GSTA4−/− compared with EtOH WT mice ( P < 0.05). EtOH PPAR-α−/− mice had increased steatosis, serum alanine aminotransferase (ALT), and hepatic CD3+ T cell populations and elevated mRNA encoding CD14, CXCL2, TNF-α, IL-6, CD138, transforming growth factor-β, platelet-derived growth factor receptor-β (PDGFR-β), matrix metalloproteinase (MMP)-9, MMP-13, α-SMA, and collagen type 1 compared with EtOH WT mice. EtOH-fed dKO mice displayed elevation of periportal hepatic 4-hydroxynonenal adducts and serum antibodies against malondialdehyde adducts compared with EtOH feeding of GSTA4−/−, PPAR-α−/−, and WT mice ( P < 0.05). ALT was higher in EtOH dKO mice compared with all other groups ( P < 0.001). EtOH-fed dKO mice displayed elevated mRNAs for TNF-α and CD14, histological evidence of fibrosis, and increased PDGFR, MMP-9, and MMP-13 mRNAs compared with the EtOH GSTA4−/− or EtOH PPAR-α−/− genotype ( P < 0.05). These findings demonstrate the central role lipid peroxidation plays in mediating progression of alcohol-induced necroinflammatory liver injury, stellate cell activation, matrix remodeling, and fibrosis.

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Section: Methodsmentioning

confidence: 99%

“…Fibrosis was examined by staining fixed liver sections with picrosirius red to detect collagen (20). Positive staining was observed in the parenchyma in EtOH-treated PPAR-␣Ϫ/Ϫ and dKO mice, especially the latter (Fig.…”

Section: Inflammation and Infiltrationmentioning

confidence: 99%

Increased 4-hydroxynonenal protein adducts in male GSTA4–4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease

Ronis

Mercer

Gannon

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Environmental factors including dietary habits, lifestyle choices, and even drug therapeutics play important roles in most human cancers (3)(4)(5), including excessive alcohol consumption corresponding to HCC (6,7). Plant drugs derived from Aristolochia spp.…”

Section: Introductionmentioning

confidence: 99%

Hepatic Premalignant Alterations Triggered by Human Nephrotoxin Aristolochic Acid I in Canines

Jin

et al. 2016

Cancer Prevention Research

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Aristolochic acid I (AAI) existing in plant drugs from Aristolochia species is an environmental human carcinogen associated with urothelial cancer. Although gene association network analysis demonstrated gene expression profile changes in the liver of human TP53 knock-in mice after acute AAI exposure, to date, whether AAI causes hepatic tumorigenesis is still not confirmed. Here, we show that hepatic premalignant alterations appeared in canines after a 10-day AAI oral administration (3 mg/kg/day). We observed c-Myc oncoprotein and oncofetal RNA-binding protein Lin28B overexpressions accompanied by cancer progenitor-like cell formation in the liver by AAI exposure. Meanwhile, we found that forkhead box O1 (FOXO1) was robustly phosphorylated, thereby shuttling into the cytoplasm of hepatocytes. Furthermore, utilizing microarray and qRT-PCR analysis, we confirmed that microRNA expression significantly dysregulated in the liver treated with AAI. Among them, we particularly focused on the members in let-7 miRNAs and miR23a clusters, the downstream of c-Myc and IL6 receptor (IL6R) signaling pathway linking the premalignant alteration. Strikingly, when IL6 was added in vitro, IL6R/NF-kB signaling activation contributed to the increase of FOXO1 phosphorylation by the let-7b inhibitor. Therefore, it highlights the new insight into the interplay of the network in hepatic tumorigenesis by AAI exposure, and also suggests that anti-premalignant therapy may be crucial for preventing AAI-induced hepatocarcinogenesis. Cancer Prev Res; 9(4); 324-34. Ó2016 AACR.

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“…10,11 The liquid diets were purchased from Dyets Inc., Bethlehem, PA. The protein source in the liquid diets was either casein (CAS) (n ¼ 22) or SPI (n ¼ 23).…”

Section: Experimental Animalsmentioning

confidence: 99%

“…Á C T for each target gene was calculated as C T for the target gene minus the average C T for the five normalizer genes included in the arrays. Gene expression for individual genes was assessed by two-step quantitative RT-PCR as described 11 or by one-step quantitative RT-PCR using a Power SYBR Green RNA-to-C T 1-Step Kit (Applied Biosystems, Foster City, CA). Expression was expressed relative to the expression of OAZ1, 36B4, or GADPH.…”

Section: Gene Expressionmentioning

confidence: 99%

Soy protein isolate inhibits hepatic tumor promotion in mice fed a high-fat liquid diet

Mercer

Pulliam

Pedersen

et al. 2017

Exp Biol Med (Maywood)

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The impact of dietary components on cancer is a topic of great interest for both the general public and the scientific community. Liver cancer is currently the second leading form of cancer deaths worldwide. Our study has addressed the effect of the protein source on hepatic tumor promotion in a mouse model reflecting aspects of non-alcoholic fatty liver disease (NAFLD). A high-fat liquid diet with casein as the protein source promotes hepatic injury and tumor promotion in diethylnitrosamine-treated mice. Replacing casein with a soy protein isolate led to a pronounced diminishment of tumor promotion and associated hepatic injury and inflammation. The study thus demonstrates that a dietary protein source can have beneficial, preventative effects on hepatic tumor promotion. AbstractAlcoholic and nonalcoholic fatty liver diseases are risk factors for development of hepatocellular carcinoma, but the underlying mechanisms are poorly understood. On the other hand, ingestion of soy-containing diets may oppose the development of certain cancers. We previously reported that replacing casein with a soy protein isolate reduced tumor promotion in the livers of mice with alcoholic liver disease after feeding a high fat ethanol liquid diet following initiation with diethylnitrosamine. Feeding soy protein isolate inhibited processes that may contribute to tumor promotion including inflammation, sphingolipid signaling, and Wnt/b-catenin signaling. We have extended these studies to characterize liver tumor promotion in a model of nonalcoholic fatty liver disease produced by chronic feeding of high-fat liquid diets in the absence of ethanol. Mice treated with diethylnitrosamine on postnatal day 14 were fed a high-fat liquid diet made with casein or SPI as the sole protein source for 16 weeks in adulthood. Relative to mice fed normal chow, a high fat/casein diet led to increased tumor promotion, hepatocyte proliferation, steatosis, and inflammation. Replacing casein with soy protein isolate counteracted these effects. The high fat diets also resulted in a general increase in transcripts for Wnt/b-catenin pathway components, which may be an important mechanism, whereby hepatic tumorigenesis is promoted. However, soy protein isolate did not block Wnt signaling in this nonalcoholic fatty liver disease model. We conclude that replacing casein with soy protein isolate blocks development of steatosis, inflammation, and tumor promotion in diethylnitrosamine-treated mice fed high fat diets.

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Alcohol Consumption Promotes Diethylnitrosamine-Induced Hepatocarcinogenesis in Male Mice through Activation of the Wnt/β-Catenin Signaling Pathway

Cited by 45 publications

References 54 publications

Increased 4-hydroxynonenal protein adducts in male GSTA4–4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease

Increased 4-hydroxynonenal protein adducts in male GSTA4–4/PPAR-α double knockout mice enhance injury during early stages of alcoholic liver disease

Hepatic Premalignant Alterations Triggered by Human Nephrotoxin Aristolochic Acid I in Canines

Soy protein isolate inhibits hepatic tumor promotion in mice fed a high-fat liquid diet

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