Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma.
Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma.
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DOI：
10.1136/gutjnl-2017-314061
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发表时间：
2018-09
期刊：
影响因子：
24.5
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Kim W;Khan SK;Liu Y;Xu R;Park O;He Y;Cha B;Gao B;Yang Y
Hippo信号通路是近年来发现的一种重要的肿瘤抑制通路，在抑制肝细胞增殖、存活和肝细胞癌（HCC）形成中起着关键作用。Hippo激酶（Mst 1和Mst 2）通过抑制雅普/Taz转录活性来抑制HCC增殖。由于人类HCC主要由慢性肝脏炎症驱动，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。我们通过删除肝细胞中的Mst 1和Mst 2建立了遗传性HCC模型。通过分子、细胞和流式细胞术分析、免疫组化和单核细胞趋化蛋白1（Mcp 1）或雅普基因缺失来表征该模型中炎症反应的功能。通过免疫组织化学分析人HCC数据库和人HCC样品。肝细胞中Mst 1和Mst 2的基因缺失（DKO）导致HCC的发展、Mcp 1表达的高度上调和具有混合M1和M2表型的巨噬细胞的大量浸润。在DKO小鼠中，Mcp 1的大片段缺失或缺失显著降低了肝脏炎症和HCC的发展。此外，去除雅普后，Mst 1/Mst 2 DKO小鼠的Mcp 1表达诱导消失，肝脏生长恢复正常。最后，我们发现MCP 1是肝细胞中雅普的直接转录靶点，并确定了人HCC中雅普靶点和Mcp-1之间的强基因表达相关性。肝细胞中的Hippo信号通过抑制Yap依赖的Mcp 1表达来抑制促肿瘤微环境形成期间的巨噬细胞浸润，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。
Hippo signaling 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 signaling inhibits HCC by shaping its inflammatory microenvironment. We have established a genetic HCC model by deleting Mst1 and Mst2 in hepatocytes. Functions of inflammatory responses in this model were characterized 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 analyzed by immunohistochemistry. 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. Macrophages 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. Hippo signaling in hepatocytes maintain normal liver growth by suppressing macrophage infiltration during pro-tumoral microenvironment formation through the inhibition of Yap-dependent Mcp1 expression, providing new targets and strategies to treat HCCs.
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影响因子：
10.5
作者：
Guo X;Zhao Y;Yan H;Yang Y;Shen S;Dai X;Ji X;Ji F;Gong XG;Li L;Bai X;Feng XH;Liang T;Ji J;Chen L;Wang H;Zhao B
通讯作者：
Zhao B
影响因子：
64.8
作者：
Gomez Perdiguero E;Klapproth K;Schulz C;Busch K;Azzoni E;Crozet L;Garner H;Trouillet C;de Bruijn MF;Geissmann F;Rodewald HR
通讯作者：
Rodewald HR
影响因子：
5.8
作者：
Dixon LJ;Barnes M;Tang H;Pritchard MT;Nagy LE
通讯作者：
Nagy LE
影响因子：
11.2
作者：
Movahedi, Kiavash;Laoui, Damya;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
32.4
作者：
Noy, Roy;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.