Objective Hippo signalling is a recently identified major oncosuppressive pathway that plays critical roles in inhibiting hepatocyte proliferation, survival and hepatocellular carcinoma (HCC) formation. Hippo kinase (Mst1 and Mst2) inhibits HCC proliferation by suppressing Yap/Taz transcription activities. As human HCC is mainly driven by chronic liver inflammation, it is not clear whether Hippo signalling inhibits HCC by shaping its inflammatory microenvironment. Design We have established a genetic HCC model by deleting Mst1 and Mst2 in hepatocytes. Functions of inflammatory responses in this model were characterised by molecular, cellular and FACS analysis, immunohistochemistry and genetic deletion of monocyte chemoattractant protein-1 (Mcp1) or Yap. Human HCC databases and human HCC samples were analysed by immunohistochemistry. Results Genetic deletion of Mst1 and Mst2 in hepatocytes (DKO) led to HCC development, highly upregulated Mcp1 expression and massive infiltration of macrophages with mixed M1 and M2 phenotypes. Macrophage ablation or deletion of Mcp1 in DKO mice markedly reduced hepatic inflammation and HCC development. Moreover, Yap removal abolished induction of Mcp1 expression and restored normal liver growth in the Mst1/Mst2 DKO mice. Finally, we showed that MCP1 is a direct transcription target of YAP in hepatocytes and identified a strong gene expression correlation between YAP targets and MCP-1 in human HCCs. Conclusions Hippo signalling in hepatocytes maintains normal liver growth by suppressing macrophage infiltration during protumoural microenvironment formation through the inhibition of Yap-dependent Mcp1 expression, providing new targets and strategies to treat HCCs.

中文翻译：

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肝河马信号抑制原肿瘤微环境抑制肝细胞癌

目的 Hippo 信号传导是最近发现的主要肿瘤抑制通路，在抑制肝细胞增殖、存活和肝细胞癌 (HCC) 形成方面起着关键作用。Hippo 激酶（Mst1 和 Mst2）通过抑制 Yap/Taz 转录活动来抑制 HCC 增殖。由于人类 HCC 主要由慢性肝脏炎症驱动，目前尚不清楚 Hippo 信号是否通过塑造其炎症微环境来抑制 HCC。设计 我们通过删除肝细胞中的 Mst1 和 Mst2 建立了遗传 HCC 模型。该模型中炎症反应的功能通过分子、细胞和 FACS 分析、免疫组织化学和单核细胞趋化蛋白 1 (Mcp1) 或 Yap 的基因缺失来表征。通过免疫组织化学分析人类 HCC 数据库和人类 HCC 样本。结果 肝细胞 (DKO) 中 Mst1 和 Mst2 的基因缺失导致 HCC 发展、高度上调 Mcp1 表达和具有混合 M1 和 M2 表型的巨噬细胞的大量浸润。DKO 小鼠中巨噬细胞消融或 Mcp1 的缺失显着减少了肝脏炎症和 HCC 的发展。此外，去除 Yap 消除了 Mcp1 表达的诱导，并恢复了 Mst1/Mst2 DKO 小鼠的正常肝脏生长。最后，我们发现 MCP1 是肝细胞中 YAP 的直接转录靶标，并确定了 YAP 靶标与人类 HCC 中 MCP-1 之间的强烈基因表达相关性。结论 肝细胞中的 Hippo 信号通过抑制 Yap 依赖性 Mcp1 表达抑制肿瘤微环境形成过程中的巨噬细胞浸润，从而维持正常肝脏生长，