Chronic ethanol feeding accelerates hepatocellular carcinoma progression in a sex-dependent manner in a mouse model of hepatocarcinogenesis.
Chronic ethanol feeding accelerates hepatocellular carcinoma progression in a sex-dependent manner in a mouse model of hepatocarcinogenesis.
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DOI：
10.1111/j.1530-0277.2011.01660.x
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发表时间：
2012-04
期刊：
影响因子：
--
通讯作者：
McKillop IH
中科院分区：
文献类型：
--
作者：
Brandon-Warner E;Walling TL;Schrum LW;McKillop IH
长期饮酒会增加患肝硬变和肝细胞癌的风险。虽然在乙醇诱导的肝损伤-肝细胞癌的易感性方面存在性别差异，但对乙醇对肿瘤进展的影响知之甚少。给新生雄性和雌性小鼠一次性注射二乙基亚硝胺(DEN)。16周或40周后，将动物置于10/20%(v/v)乙醇饮用水(Etoh-DW；隔天)中，连续8周。在研究结束时，分析肝组织和血清的肝脏病理/功能和细胞因子的表达。在雄性和雌性小鼠中，DEN可重复性地诱发肝脏病灶/肿瘤。乙醇可降低肝功能，增加肝脏损伤，但乙醇本身并不能诱导肝细胞癌形成。在DEN启动的Etoh-DW动物中，乙醇显著增加了肿瘤的发病率和负担，但仅在雄性小鼠中。雄性和雌性小鼠(±DEN)在尸检时显示出相似的血液酒精含量，但雄性小鼠的肝脏损伤增加和肝功能/抗氧化能力降低的程度明显更大。肝脏Th1、Th2或T调节因子的mRNA分析显示，在乙醇、DEN-启动和DEN+Etoh-DW的反应中，雄性小鼠的Smad3显著高于雌性小鼠。这些数据表明，在长期饮酒的情况下，雄性小鼠比雌性小鼠更容易患上肝癌。雄性小鼠肝脏免疫反应标志物的差异表明，转化生长因子β-Smad3信号的增加可能增强了这种肝癌进展模型的促进作用，这种作用受长期酒精喂养的调节。
Chronic ethanol consumption increases the risk of hepatic cirrhosis and hepatocellular carcinoma (HCC). While sex differences exist in susceptibility to ethanol-induced liver damage-HCC development, little is known about the effects of ethanol on tumor progression. Neonatal male and female mice were initiated with a single dose of diethylnitrosamine (DEN). 16 or 40 weeks later animals were placed on a 10/20% (v/v) ethanol-drinking water (EtOH-DW; alternate days) regime for 8 weeks. At study end liver tissue and serum were analyzed for liver pathology/function and cytokine expression. DEN reproducibly induced hepatic foci/tumors in male and female mice. Ethanol diminished hepatic function and increased liver damage, but ethanol alone did not induce hepatic foci-HCC formation. In DEN-initiated EtOH-DW animals, ethanol significantly increased tumor incidence and burden, but only in male mice. Male and female mice (±DEN) demonstrated comparable blood-alcohol content at necropsy, yet increased hepatic damage and diminished hepatic function/anti-oxidant capacity was significantly greater in males. Analysis of liver mRNA for Th1, Th2 or T-regulatory factors demonstrated significantly elevated SMAD3 in male compared to female mice in response to EtOH, DEN-initiation and DEN+EtOH-DW. These data demonstrate male mice are more susceptible to HCC incidence and progression in the setting of chronic ethanol feeding than females. Differences in markers of hepatic immune response in male mice suggest increased TGFβ-SMAD3 signaling may enhance promotion in this model of HCC progression, effects modulated by chronic ethanol feeding.
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影响因子：
10.4
作者：
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通讯作者：
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