PMID- 28866620 OWN - NLM STAT- MEDLINE DCOM- 20180917 LR - 20211204 IS - 1468-3288 (Electronic) IS - 0017-5749 (Print) IS - 0017-5749 (Linking) VI - 67 IP - 9 DP - 2018 Sep TI - Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. PG - 1692-1703 LID - 10.1136/gutjnl-2017-314061 [doi] AB - 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. CI - (c) Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. FAU - Kim, Wantae AU - Kim W AD - Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA. AD - Genetic Disease Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland, USA. FAU - Khan, Sanjoy Kumar AU - Khan SK AD - Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA. AD - Genetic Disease Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland, USA. FAU - Liu, Yuchen AU - Liu Y AD - Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA. FAU - Xu, Ruoshi AU - Xu R AD - Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA. AD - West China School of Stomatology, Sichuan University, Chengdu, China. FAU - Park, Ogyi AU - Park O AD - Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA. FAU - He, Yong AU - He Y AD - Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA. FAU - Cha, Boksik AU - Cha B AD - Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA. FAU - Gao, Bin AU - Gao B AD - Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA. FAU - Yang, Yingzi AU - Yang Y AD - Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts, USA. AD - Genetic Disease Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, Maryland, USA. LA - eng GR - R01 CA222571/CA/NCI NIH HHS/United States PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170902 PL - England TA - Gut JT - Gut JID - 2985108R RN - 0 (Phosphoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Transcription Factors) RN - 0 (macrophage stimulating protein) RN - 67256-21-7 (Hepatocyte Growth Factor) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Serine-Threonine Kinase 3) RN - EC 2.7.11.1 (Stk3 protein, mouse) SB - IM MH - Animals MH - Carcinoma, Hepatocellular/enzymology/*genetics/therapy MH - Cell Proliferation/genetics MH - Cell Transformation, Neoplastic MH - Hepatocyte Growth Factor/genetics MH - Hepatocytes/metabolism MH - Hippo Signaling Pathway MH - Liver Neoplasms, Experimental/enzymology/*genetics/therapy MH - Mice MH - Mice, Mutant Strains MH - Phosphoproteins/genetics MH - Protein Serine-Threonine Kinases/*genetics/metabolism MH - Proto-Oncogene Proteins/genetics MH - Serine-Threonine Kinase 3 MH - *Signal Transduction/genetics MH - Transcription Factors/genetics PMC - PMC6592016 MID - NIHMS1031142 OTO - NOTNLM OT - Cancer OT - Hepatocellular Carcinoma OT - Inflammation OT - Liver OT - Macrophages COIS- Competing interests: None declared. EDAT- 2017/09/04 06:00 MHDA- 2018/09/18 06:00 PMCR- 2019/09/01 CRDT- 2017/09/04 06:00 PHST- 2017/03/01 00:00 [received] PHST- 2017/05/30 00:00 [revised] PHST- 2017/06/09 00:00 [accepted] PHST- 2017/09/04 06:00 [pubmed] PHST- 2018/09/18 06:00 [medline] PHST- 2017/09/04 06:00 [entrez] PHST- 2019/09/01 00:00 [pmc-release] AID - gutjnl-2017-314061 [pii] AID - 10.1136/gutjnl-2017-314061 [doi] PST - ppublish SO - Gut. 2018 Sep;67(9):1692-1703. doi: 10.1136/gutjnl-2017-314061. Epub 2017 Sep 2.