FGF9 招募 β-连环素增加肝脏细胞外基质的合成并促进NASH驱动的HCC。
FGF9 Recruits β-Catenin to Increase Hepatic ECM Synthesis and Promote NASH-Driven HCC.
发表日期：2023 Aug 11
作者：
Lei Zhang, Qing Zhang, Da Teng, Manyu Guo, Kechao Tang, Zhenglin Wang, Xiang Wei, Li Lin, Xiaomin Zhang, Xiuyun Wang, Dake Huang, Cuiping Ren, Qingsong Yang, Wenjun Zhang, Yong Gao, Wei Chen, Yongsheng Chang, Huabing Zhang
来源：
Disease Models & Mechanisms
摘要：
大多数非酒精性脂肪性肝炎（NASH）患者通过胞外基质（ECM）积聚产生严重纤维化，这可能导致肝细胞肝癌（HCC）。成纤维细胞生长因子9（FGF9）参与多种类型的癌症，然而，在NASH驱动的HCC中FGF9的具体作用尚不完全了解。本研究发现，NASH相关HCC患者中FGF9增加。此外，本研究建立了以给予野生型小鼠高脂/高胆固醇（HFHC）饮食和低剂量四氯化碳（CCl4）处理来诱导NASH驱动的HCC小鼠模型；并确定肝部FGF9增加，伴有严重纤维化。此外，AAV介导的FGF9减少对NASH驱动的HCC小鼠模型中的肝肿瘤负担。以肝细胞特异性FGF9转基因小鼠（FGF9Alb）在未经CCl4处理的HFHC饮食下加以喂养，显示其肝部胞外基质和肿瘤负担增加。然而，XAV-939治疗阻断了FGF9Alb小鼠在HFHC饮食下胞外基质积聚和NASH驱动的HCC的发展。分子机制研究显示，FGF9通过β-连环蛋白依赖的方式刺激胞外基质相关基因的表达；FGF9通过ERK1/2-GSK-3β信号通路对β-连环蛋白的稳定性产生影响。总之，数据为FGF9在NASH驱动的HCC发病机制中的关键作用提供了证据；其通过胞外基质途径促进肿瘤形成。© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.
Most nonalcoholic steatohepatitis (NASH) patients develop severe fibrosis through extracellular matrix (ECM) accumulation, which can lead to hepatocellular carcinoma (HCC). Fibroblast growth factor 9 (FGF9) is involved in serial types of cancer; however, the specific role of FGF9 in NASH-driven HCC is not fully understood. This study finds that FGF9 is increased in patients with NASH-associated HCC. Furthermore, NASH-driven HCC mice models by feeding wildtype mice with high-fat/high-cholesterol (HFHC) diet and low dose carbon tetrachloride (CCl4 ) treatment is established; and identified that hepatic FGF9 is increased; with severe fibrosis. Additionally, AAV-mediated knockdown of FGF9 reduced the hepatic tumor burden of NASH-driven HCC mice models. Hepatocyte-specific FGF9 transgenic mice (FGF9Alb ) fed with a HFHC diet without CCl4 treatment exhibited an increased hepatic ECM and tumor burden. However, XAV-939 treatment blocked ECM accumulation and NASH-driven HCC in FGF9Alb mice fed with HFHC diet. Molecular mechanism studies show that FGF9 stimulated the expression of ECM related genes in a β-catenin dependent manner; and FGF9 exerts its effect on β-catenin stability via the ERK1/2-GSK-3β signaling pathway. In summary, the data provides evidence for the critical role of FGF9 in NASH-driven HCC pathogenesis; wherein it promotes the tumors formation through the ECM pathway.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.