Induction of steatohepatitis and liver tumorigenesis by enforced Snail expression in hepatocytes
Induction of steatohepatitis and liver tumorigenesis by enforced Snail expression in hepatocytes
复制标题
通过在肝细胞中强制表达 Snail 诱导脂肪性肝炎和肝脏肿瘤发生
DOI：
10.1016/j.ajpath.2020.02.005
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
A.
中科院分区：
文献类型：
--
作者：
Miura;S. and Suzuki;A.
Snail是一种转录因子，调节许多与发育、内稳态和疾病有关的细胞事件。在肝细胞癌中，Snail诱导上皮细胞向间充质细胞的转变，使肿瘤细胞在肝细胞癌的进展和恶变过程中具有侵袭性。在肝癌小鼠模型中观察到的蜗牛激活表明，它不仅参与了肝细胞癌的进展，而且还参与了肝细胞癌的发生。然而，目前尚不清楚Snail是否直接参与了肝细胞癌的启动，或者它是否支持其他癌基因促进的肝细胞癌的启动。在这项研究中，我们建立了肝脏特异性和肝细胞特异性Snail过表达的小鼠模型，以显示Snail在肝脏动态平衡和疾病中的独立作用。Snail过度表达可导致大鼠肝脏和肝细胞肿大，肝内炎性细胞浸润，肝细胞内脂质积聚，血清丙氨酸氨基转移酶和胆汁酸显著升高，胆红素积聚导致组织黄染，肝肿瘤发生。Snail过表达抑制紧密连接成分Claudins和occludin以及胆汁酸代谢相关蛋白的mRNA表达，破坏肝细胞间形成的胆小管，并从肝细胞排泄异常数量的异常胆汁酸。总之，在肝细胞中强制表达Snail足以通过破坏胆小管和肝脏中胆汁酸的平衡来诱导脂肪性肝炎和肝肿瘤的发生。
Snail is a transcription factor that regulates many cellular events involved in development, homeostasis, and disease. In hepatocellular carcinoma (HCC), Snail induces epithelial-to-mesenchymal transition that confers invasive properties on tumor cells during HCC progression and malignancy. Snail activation observed in HCC mouse models suggests its involvement not only in progression, but also onset of HCC. However, it remains unclear whether Snail directly contributes to HCC initiation or whether it supports HCC initiation promoted by other oncogenes. In this study, we generated mouse models for liver-specific and hepatocyte-specific overexpression ofSnailto show the independent roles of Snail in liver homeostasis and disease. EnforcedSnailexpression resulted in liver and hepatocyte enlargement, inflammatory cell infiltration in the liver, lipid accumulation in hepatocytes, substantial increases in serum alanine aminotransferase and bile acids, yellow discoloration of tissues caused by bilirubin accumulation, and liver tumorigenesis.Snailoverexpression suppressed mRNA expression of the tight junction components claudins and occludin and that of proteins associated with bile acid metabolism, leading to disruption of the biliary canaliculus formed among hepatocytes and excretion of abnormal amounts of unusual bile acids from hepatocytes. In conclusion, enforcedSnailexpression in hepatocytes is sufficient for induction of steatohepatitis and liver tumorigenesis through disruption of the biliary canaliculus and bile acid homeostasis in the liver.