Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma.

Abstract

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 <i>Mst1</i> and <i>Mst2</i> 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 (<i>Mcp1</i>) or <i>Yap</i>. 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 <i>Mcp1</i> 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, <i>Yap</i> 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 <i>Mcp1</i> expression, providing new targets and strategies to treat HCCs.