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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways.
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Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways.

机译：小鼠肝硬化诱导肝细胞上皮间质转化和生存信号通路的改变。

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Hepatocytes that reside in a chronically-injured liver have altered growth responses compared to hepatocytes in normal liver. Transforming growth factor beta (TGFbeta) is upregulated in the cirrhotic liver, and cirrhotic hepatocytes, unlike normal hepatocytes exposed to this cytokine, exhibit decreased apoptosis. In fetal hepatocytes, TGFbeta also induces epithelial-mesenchymal transition (EMT) and signaling changes in cell survival pathways. Here, chronic murine liver injury was induced by twice-weekly carbon tetrachloride administration for 8 weeks. Normal liver-derived hepatocytes (NLDH) and cirrhotic liver-derived hepatocytes (CLDH) were examined for EMT and the small mothers against decapentaplegic homolog (Smad), phosphatidylinositol-3-kinase (PI3K/Akt), and mitogen activated protein kinase (MAPK) pathways were investigated. Immunofluorescence imaging of cirrhotic livers demonstrated increased vimentin expression, which was confirmed by immunoblot analysis. In vitro, CLDH exhibited increased vimentin and type 1 collagen expression within cellular extensions consistent with EMT. Treatment with TGFbeta augmented the EMT response in CLDH. In contrast, untreated NLDH did not display features of EMT but responded to TGFbeta with increased vimentin expression and EMT characteristics. In response to PI3K/Akt inhibition, CLDH had decreased basal and insulin-stimulated p-Akt expression and decreased apoptosis compared to NLDH. In both NLDH and CLDH, vimentin expression was dependent on PI3K/Akt activity. CLDH demonstrated increased basal p-extracellular signal-regulated kinase expression that was independent of Smad and PI3K/Akt signaling. Inhibition of the MAPK pathway produced a marked increase in CLDH apoptosis. CONCLUSION: CLDH have increased vimentin and type 1 collagen expression and morphologic features consistent with EMT. In addition, compared to NLDH, the cellular signaling phenotype of CLDH changes from a MAPK-independent pathway to a MAPK-dependent cell survival pathway. These findings may have clinical implications for chemoprevention of hepatocellular carcinoma in the cirrhotic liver.
机译：与正常肝脏中的肝细胞相比，驻留在慢性受伤的肝脏中的肝细胞的生长反应发生了变化。肝硬化肝脏中的转化生长因子β（TGFbeta）被上调，与暴露于这种细胞因子的正常肝细胞不同，肝硬化肝细胞的凋亡减少。在胎儿肝细胞中，TGFβ还诱导上皮-间充质转化（EMT）并发出细胞存活途径变化的信号。在此，通过每周两次两次四氯化碳持续8周来诱发慢性鼠肝损伤。检查了正常肝源性肝细胞（NLDH）和肝硬化性肝源性肝细胞（CLDH）的EMT以及小型母亲的抗能力障碍同系物（Smad），磷脂酰肌醇3-激酶（PI3K / Akt）和促分裂原活化蛋白激酶（MAPK） ）的途径进行了调查。肝硬化肝的免疫荧光成像显示波形蛋白表达增加，这通过免疫印迹分析得到证实。在体外，CLDH在与EMT一致的细胞扩展内显示波形蛋白和1型胶原蛋白表达增加。 TGFbeta的治疗增强了CLDH中的EMT反应。相反，未经处理的NLDH没有显示EMT的特征，但是对TGFbeta的反应是波形蛋白表达和EMT特性增加。响应PI3K / Akt抑制，与DHDH相比，CLDH的基础和胰岛素刺激的p-Akt表达降低，凋亡减少。在NLDH和CLDH中，波形蛋白的表达均依赖于PI3K / Akt活性。 CLDH证明增加的基础p-细胞外信号调节激酶表达独立于Smad和PI3K / Akt信号传导。 MAPK途径的抑制产生CLDH细胞凋亡的明显增加。结论：CLDH具有增加的波形蛋白和1型胶原蛋白的表达，其形态学特征与EMT一致。此外，与NLDH相比，CLDH的细胞信号表型从MAPK依赖性途径变为MAPK依赖性细胞存活途径。这些发现可能对肝硬化肝细胞癌的化学预防具有临床意义。

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