Alcoholic hepatitis accelerates early hepatobiliary cancer by increasing stemness and miR-122-mediated HIF-1α activation.
Alcoholic hepatitis accelerates early hepatobiliary cancer by increasing stemness and miR-122-mediated HIF-1α activation.
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DOI：
10.1038/srep21340
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发表时间：
2016-02-18
影响因子：
4.6
通讯作者：
Szabo G
中科院分区：
文献类型：
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作者：
Ambade A;Satishchandran A;Szabo G
酒精相关性肝细胞癌（HCC）是伴随着晚期酒精性肝病和肝纤维化而发展的。利用成年小鼠，我们评估酒精性脂肪性肝炎对二乙基亚硝胺（DEN）引发的早期肝胆癌的影响。在这里，我们表明，酒精喂养的DEN注射小鼠有较高的ALT和肝脏与体重比相比，成对喂养的DEN注射小鼠。酒精喂养导致脂肪性肝炎，表现为促炎细胞因子和纤维化基因增加。酒精+DEN小鼠的MRI和肝脏组织学显示肝胆囊肿、早期肝肿瘤和血清甲胎蛋白增加。与对照组相比，在酒精喂养的DEN注射小鼠的肝脏中，增殖标记物（BrdU，细胞周期蛋白D1，p53）和癌症干细胞标记物（CD 133和nanog）显著上调。在有肿瘤的肝脏中，观察到miR-122表达的缺失以及miR-122靶点HIF-1α的显著上调。我们得出结论，酒精性脂肪性肝炎通过上调炎症、细胞增殖、干性和miR-122丢失加速具有HCC特征性分子特征的肝胆肿瘤。
Alcohol-related hepatocellular carcinoma (HCC) develops with advanced alcoholic liver disease and liver fibrosis. Using adult mice, we evaluate the effect of alcoholic steatohepatitis on early hepatobiliary carcinoma after initiation by diethyl-nitrosamine (DEN). Here we show that alcohol-fed DEN-injected mice have higher ALT and liver-to-body weight ratio compared to pair-fed DEN-injected mice. Alcohol feeding results in steatohepatitis indicated by increased pro-inflammatory cytokines and fibrotic genes. MRI and liver histology of alcohol+DEN mice shows hepatobiliary cysts, early hepatic neoplasia and increase in serum alpha-fetoprotein. Proliferation makers (BrdU, cyclin D1, p53) and cancer stem cell markers (CD133 and nanog) are significantly up-regulated in livers of alcohol-fed DEN-injected mice compared to controls. In livers with tumors, loss of miR-122 expression with a significant up-regulation of miR-122 target HIF-1α is seen. We conclude that alcoholic steatohepatitis accelerates hepatobiliary tumors with characteristic molecular features of HCC by up-regulating inflammation, cell proliferation, stemness, and miR-122 loss.