Article Text

PDF
Original Article
Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma
  1. Wantae Kim1,2,
  2. Sanjoy Kumar Khan1,2,
  3. Yuchen Liu1,
  4. Ruoshi Xu1,3,
  5. Ogyi Park4,
  6. Yong He4,
  7. Boksik Cha5,
  8. Bin Gao4,
  9. Yingzi Yang1,2
  1. 1Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA
  2. 2Genetic Disease Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland, USA
  3. 3West China School of Stomatology, Sichuan University, Chengdu, China
  4. 4Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
  5. 5Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  1. Correspondence to Dr Bin Gao, Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD; ; bgao{at}mail.nih.gov and Dr. Yingzi Yang, Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA. USA; ; yingzi_yang{at}hsdm.harvard.edu

Abstract

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.

  • Liver
  • Inflammation
  • Cancer
  • Hepatocellular Carcinoma
  • Macrophages

Statistics from Altmetric.com

Footnotes

  • Contributors WK, SK, YL and RX designed and performed genetic crosses, tissue sampling and mouse experiments. OP designed and performed experiment to analyse Mcp1 secretion from serum and primary hepatocytes. BC analysed Mcp1 promoter and helped with ChIP-qPCR assay analysis. YH cut human HCC sections. WK, SK, YL, BG and YY wrote and reviewed manuscript. BG and YY designed and supervised manuscript.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.