Autophagy mediated by the HGF/Met/JNK signaling pathway is involved in carcinogenesis of liver cirrhosis
- Author:
- No author available
- Journal Title:
- World Chinese Journal of Digestology
- Issue:
- 20
- DOI:
- 10.11569/wcjd.v29.i20.1158
- Key Word:
- HGF/Met/JNK信号通路;自噬;c-Met抑制剂;肝硬化
Abstract： 背景 肝癌干细胞样细胞(hepatocarcinoma stem cell-like cells,CSCs)具有较强的自我更新和肿瘤发生能力,在肝硬化进展至肝癌的进程发挥关键作用.我们将肝脏Axin2+CD90+细胞鉴定为肝硬化的CSCs,并观察了HGF/Met/JN信号通路介导的细胞自噬在肝硬化进展至肝癌期间的作用.目的明确肝细胞生长因子(hepatocyte growth factor,HGF)/Met/JNK信号通路介导的细胞自噬在肝硬化癌变进程中的作用.方法 从肝血管瘤患者中共收集8例非肝硬化手术标本;2007-09,在本院收集了 18例酒精相关,30例慢性乙型肝炎相关肝硬化活检样本.这些患者随访至2015-12.来自患者的3例外科肝癌样本与酒精相关的肝硬化,通过手术收集来自乙型肝炎相关肝硬化患者的8个肝癌样本.8 wk龄雄性SD大鼠每周两次腹膜内注射50 mg/kg二乙基亚硝胺持续8 wk建立肝硬化模型.Western-blotting检测人和大鼠进行的组织自噬状态、HGF的水平及HGF/Met/JNK信号途径分子的变化.采用c-Met抑制剂EMD1214063治疗肝硬化大鼠并评估细胞增殖和凋亡,同时评估HGF/Met/JNK信号途径分子的变化.结果 相较于正常肝组织对照,肝硬化患者的自噬水平显著升高(全部P＜0.05),而自噬水平的下降与肝硬化进展为肝癌有关;同时,这些肝硬化异常自噬样本中HGF的产生显著增加.肝硬化肝脏根据自噬状态和HGF表达首先分层后发现p-Met、t-Met及p-JNK水平在自噬增强的Axin2阳性细胞中显著升高(全部P＜0.05).治疗8 wk和11 wk后细胞增殖显著减少(全部P＜0.05),而TUNEL染色的结果显示细胞的c-Met抑制剂EMD1214063对肝细胞的凋亡并无明显影响.在第8周和第11周使用来自对照和EMD1214063处理组的全肝裂解物的Western印迹分析显示p-Met、p-JNK及HGF在11 wk的大鼠中显著降低,而t-Met、p-JNK及HGF在8 wk的大鼠中显著降低.结论 HGF/Met/JNK信号通路介导的细胞自噬参与到肝硬化癌变进程中,并且c-Met抑制剂能够在肝硬化进程中发挥治疗作用.
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