Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
Genetic Disease Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland, USA.
Gut. 2018 Sep;67(9):1692-1703. doi: 10.1136/gutjnl-2017-314061. Epub 2017 Sep 2.
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.
We have established a genetic HCC model by deleting and 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 () or . Human HCC databases and human HCC samples were analysed by immunohistochemistry.
Genetic deletion of Mst1 and Mst2 in hepatocytes (DKO) led to HCC development, highly upregulated 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, 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.
Hippo signalling in hepatocytes maintains normal liver growth by suppressing macrophage infiltration during protumoural microenvironment formation through the inhibition of Yap-dependent expression, providing new targets and strategies to treat HCCs.
Hippo 信号通路是最近发现的主要抑癌途径，在抑制肝细胞增殖、存活和肝细胞癌（HCC）形成方面发挥着关键作用。 Hippo 激酶（Mst1 和 Mst2）通过抑制 Yap/Taz 转录活性抑制 HCC 增殖。由于人类 HCC 主要由慢性肝炎症驱动，因此尚不清楚 Hippo 信号是否通过塑造其炎症微环境来抑制 HCC。
我们通过在肝细胞中删除 和 建立了遗传 HCC 模型。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（）或 的基因缺失来研究该模型中的炎症反应功能。分析了人类 HCC 数据库和人类 HCC 样本的免疫组织化学。
肝细胞中 Mst1 和 Mst2 的基因缺失（DKO）导致 HCC 发展， 表达显著上调，巨噬细胞大量浸润，具有 M1 和 M2 混合表型。巨噬细胞消融或 DKO 小鼠中 Mcp1 的缺失显著减少了肝炎症和 HCC 发展。此外， 去除消除了诱导 Mcp1 表达，并使 Mst1/Mst2 DKO 小鼠的正常肝脏生长恢复正常。最后，我们表明 MCP1 是肝细胞中 Yap 的直接转录靶标，并在人类 HCC 中鉴定出 YAP 靶标和 MCP-1 之间的强烈基因表达相关性。
肝细胞中的 Hippo 信号通过抑制 Yap 依赖性 表达来抑制肿瘤前期微环境形成过程中的巨噬细胞浸润，从而维持正常的肝脏生长，为治疗 HCC 提供了新的靶点和策略。
