Alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis in male mice through activation of the Wnt/β-catenin signaling pathway.
Alcohol consumption promotes diethylnitrosamine-induced hepatocarcinogenesis in male mice through activation of the Wnt/β-catenin signaling pathway.
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DOI：
10.1158/1940-6207.capr-13-0444-t
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发表时间：
2014-07
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影响因子：
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通讯作者：
Ronis MJ
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文献类型：
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作者：
Mercer KE;Hennings L;Sharma N;Lai K;Cleves MA;Wynne RA;Badger TM;Ronis MJ
尽管酒精对肝脏的影响已被广泛研究，但酒精导致肝癌的复杂机制尚不清楚。乙醇（EtOH）代谢通过增加肝细胞增殖促进肿瘤生长。在这项研究中，我们建立了一种慢性摄取乙基亚硝胺促进肿瘤的小鼠模型，在注射化学致癌物二乙基亚硝胺（DEN） 46天后开始摄取乙基亚硝胺，持续16周。当最终EtOH浓度为总热量的28%时，我们观察到EtOH+DEN组中每只小鼠的肿瘤前病灶和肝脏肿瘤总数显著增加，与相应的配对喂养(PF)+DEN和chow+DEN对照组相比。我们还观察到，与PF+DEN对照组相比，EtOH+DEN小鼠的非肿瘤肝脏切片中肝细胞增殖增加了4倍（p<0.05），活性β-catenin的细胞质染色增加。在酒精性肝病大鼠模型中，我们发现肝细胞增殖增加（p<0.05）；视黄醇和视黄酸储存耗尽（p<0.05）；β-catenin和磷酸化糖原合成酶激酶3β (p- gsk3 β)胞浆和细胞核表达增加（p<0.05）， Wnt7a mRNA表达显著上调，谷氨酰胺合成酶（GS）、细胞周期蛋白D1、Wnt1诱导信号通路蛋白（WISP1）、基质金属蛋白酶-7 （MMP7）等β-catenin靶点表达增加（p<0.05）。这些数据表明，慢性EtOH消耗激活Wnt/β-catenin信号通路，增加肝细胞增殖，从而促进肝脏初始损伤后的肿瘤发生。
Although alcohol effects within the liver have been extensively studied, the complex mechanisms by which alcohol causes liver cancer are not well understood. It has been suggested that ethanol (EtOH) metabolism promotes tumor growth by increasing hepatocyte proliferation. In this study, we developed a mouse model of tumor promotion by chronic EtOH consumption in which EtOH feeding began 46 days post-injection of the chemical carcinogen diethylnitrosamine (DEN) and continued for 16 weeks. With a final EtOH concentration of 28% of total calories, we observed a significant increase in the total number of preneoplastic foci and liver tumors per mouse in the EtOH+DEN group compared to corresponding pair-fed (PF)+DEN and chow+DEN control groups. We also observed a 4-fold increase in hepatocyte proliferation (p<0.05) and increased cytoplasmic staining of active-β-catenin in non-tumor liver sections from EtOH+DEN mice compared to PF+DEN controls. In a rat model of alcohol-induced liver disease, we found increased hepatocyte proliferation (p<0.05); depletion of retinol and retinoic acid stores (p<0.05); increased expression of cytosolic and nuclear expression of β-catenin (p<0.05) and phosphorylated-glycogen synthase kinase 3 β (p-GSK3β, p<0.05; significant up-regulation in Wnt7a mRNA expression; and increased expression of several β-catenin targets, including, glutamine synthetase (GS), cyclin D1, Wnt1 inducible signaling pathway protein (WISP1), and matrix metalloproteinase-7 (MMP7), p<0.05. These data suggest that chronic EtOH consumption activates the Wnt/β-catenin signaling pathways to increase hepatocyte proliferation, thus promoting tumorigenesis following an initiating insult to the liver.