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Hepatology
Original research
TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms
  1. Aitor Esparza-Baquer1,
  2. Ibone Labiano1,
  3. Omar Sharif2,3,
  4. Aloña Agirre-Lizaso1,
  5. Fiona Oakley4,
  6. Pedro M Rodrigues1,5,
  7. Ekaterina Zhuravleva6,
  8. Colm J O'Rourke6,
  9. Elizabeth Hijona1,5,
  10. Raul Jimenez-Agüero1,
  11. Ioana Riaño1,
  12. Ana Landa1,
  13. Adelaida La Casta1,
  14. Marco Y W Zaki4,7,
  15. Patricia Munoz-Garrido6,
  16. Mikel Azkargorta5,8,
  17. Felix Elortza5,8,
  18. Andrea Vogel2,3,
  19. Gernot Schabbauer2,3,
  20. Patricia Aspichueta9,
  21. Jesper B Andersen6,
  22. Sylvia Knapp10,11,
  23. Derek A Mann4,
  24. Luis Bujanda1,5,12,
  25. Jesus Maria Banales1,5,13,
  26. Maria Jesus Perugorria1,5,12,13
  1. 1 Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain
  2. 2 Institute for Vascular Biology, Center for Physiology and Pharmacology, Medical University Vienna, Vienna, Austria
  3. 3 Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria
  4. 4 Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
  5. 5 CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
  6. 6 Department of Health and Medical Sciences, Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark
  7. 7 Biochemistry Department, Faculty of Pharmacy, Minia University, Minya, Egypt
  8. 8 Proteomics Platform, CIC bioGUNE, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, Spain
  9. 9 Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Lejona, Spain
  10. 10 CeMM, Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
  11. 11 Department of Medicine I, Laboratory of Infection Biology, Medical University of Vienna, Vienna, Austria
  12. 12 Department of Medicine, Faculty of Medicine and Nursing, University of the Basque Country, UPV/EHU, Lejona, Spain
  13. 13 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  1. Correspondence to Maria Jesus Perugorria, Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, Donostia - San Sebastián, Guipuzcoa, Spain; matxus.perugorria{at}biodonostia.org; Jesus Maria Banales, Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, Donostia - San Sebastián, Guipuzcoa, Spain; jesus.banales{at}biodonostia.org

Abstract

Objective Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer usually arising on a background of chronic liver injury involving inflammatory and hepatic regenerative processes. The triggering receptor expressed on myeloid cells 2 (TREM-2) is predominantly expressed in hepatic non-parenchymal cells and inhibits Toll-like receptor signalling, protecting the liver from various hepatotoxic injuries, yet its role in liver cancer is poorly defined. Here, we investigated the impact of TREM-2 on liver regeneration and hepatocarcinogenesis.

Design TREM-2 expression was analysed in liver tissues of two independent cohorts of patients with HCC and compared with control liver samples. Experimental HCC and liver regeneration models in wild type and Trem-2-/- mice, and in vitro studies with hepatic stellate cells (HSCs) and HCC spheroids were conducted.

Results TREM-2 expression was upregulated in human HCC tissue, in mouse models of liver regeneration and HCC. Trem-2-/- mice developed more liver tumours irrespective of size after diethylnitrosamine (DEN) administration, displayed exacerbated liver damage, inflammation, oxidative stress and hepatocyte proliferation. Administering an antioxidant diet blocked DEN-induced hepatocarcinogenesis in both genotypes. Similarly, Trem-2-/- animals developed more and larger tumours in fibrosis-associated HCC models. Trem-2-/- livers showed increased hepatocyte proliferation and inflammation after partial hepatectomy. Conditioned media from human HSCs overexpressing TREM-2 inhibited human HCC spheroid growth in vitro through attenuated Wnt ligand secretion.

Conclusion TREM-2 plays a protective role in hepatocarcinogenesis via different pleiotropic effects, suggesting that TREM-2 agonism should be investigated as it might beneficially impact HCC pathogenesis in a multifactorial manner.

  • hepatocellular carcinoma
  • immune-mediated liver damage
  • liver immunology
  • liver regeneration
  • molecular carcinogenesis

Data availability statement

Data are available upon reasonable request. Email address: matxus.perugorria@biodonostia.org.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/gutjnl-2019-319227

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    Data availability statement

    Data are available upon reasonable request. Email address: matxus.perugorria@biodonostia.org.

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    Footnotes

    • AE-B and IL are joint first authors.

    • JMB and MJP are joint senior authors.

    • Twitter @andvoge, @jaboeje

    • Contributors MJP and JMB conceived, designed and coordinated the experiments. AE-B, IL, OS, AA-L, FO, PMR, EH, RJ-A, IR, AL, ALC, MYWZ, PM-G, MA, FE and MJP performed the experiments and obtained the data. AE-B, IL, OS, AA-L, FO, PMR, CJO'R, PM-G, AV, GS, PA, JBA, SK, DAM, LB, JMB and MJP analysed and interpreted the data. EZ, CJO'R and JBA analysed single-cell RNA sequencing data and performed cellular deconvolution and correlation analysis. AE-B, IL, OS, JMB and MJP wrote the manuscript. OS, SK, DAM, LB, JMB and MJP obtained funding. All authors read and approved the final manuscript.

    • Funding Spanish Ministry of Economy and Competitiveness and 'Instituto de Salud Carlos III' grants (MJP (PI14/00399, PI17/00022 and Ramon y Cajal Programme RYC-2015–17755); JMB (PI12/00380, PI15/01132, PI18/01075, Miguel Servet Programme CON14/00129 and CPII19/00008) cofinanced by 'Fondo Europeo de Desarrollo Regional' (FEDER); CIBERehd: MJP, JMB and LB), Spain; IKERBASQUE, Basque foundation for Science (MJP and JMB), Spain; 'Diputación Foral de Gipuzkoa' (MJP: DFG18/114, DFG19/081; JMB: DFG15/010, DFG16/004); BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to JMB); Department of Health of the Basque Country (MJP: 2015111100 and 2019111024; JMB: 2017111010), Euskadi RIS3 (JMB: 2016222001, 2017222014, 2018222029, 2019222054, 2020333010) Department of Industry of the Basque Country (JMB: Elkartek: KK-2020/00008) and AECC Scientific Foundation (JMB). AE-B was funded by the University of the Basque Country (UPV/EHU) (PIF2014/11) and by the short-term training fellowship Andrew K Burroughs (European Association for the Study of the Liver, EASL). IL and AA-L were funded by the Department of Education, Language Policy and Culture of the Basque Government (PRE_2016_1_0152 and PRE_2018_1_0184). OS and SK were funded by the Austrian Science Fund (FWF25801-B22, FWF-P35168 to OS and L-Mac: F 6104-B21 to SK). FO and DAM were funded by a UK Medical Research Council programme Grant MR/R023026/1. DAM was also funded by the CRUK programme grant C18342/A23390, CRUK/AECC/AIRC Accelerator Award A26813 and the MRC MICA programme grant MR/R023026/1. JBA is supported by the Danish Medical Research Council, Danish Cancer Society, Nordisk Foundation, and APM Foundation. CJO’R and PM-G are supported by Marie Sklodowska-Curie Programme and EASL Sheila Sherlock postdoctoral fellowships.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

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

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