1. TREM-2 defends the liver against hepatocellular carcinoma through multifactorial protective mechanisms.
- Author
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Esparza-Baquer A, Labiano I, Sharif O, Agirre-Lizaso A, Oakley F, Rodrigues PM, Zhuravleva E, O'Rourke CJ, Hijona E, Jimenez-Agüero R, Riaño I, Landa A, La Casta A, Zaki MYW, Munoz-Garrido P, Azkargorta M, Elortza F, Vogel A, Schabbauer G, Aspichueta P, Andersen JB, Knapp S, Mann DA, Bujanda L, Banales JM, and Perugorria MJ
- Subjects
- Adult, Aged, Animals, Carcinogenesis genetics, Carcinoma, Hepatocellular chemically induced, Carcinoma, Hepatocellular pathology, Cell Line, Tumor, Cell Proliferation, Diethylnitrosamine, Female, Gain of Function Mutation, Gene Expression, Hepatic Stellate Cells metabolism, Hepatitis metabolism, Hepatocytes pathology, Hepatocytes physiology, Humans, Liver metabolism, Liver Cirrhosis metabolism, Liver Neoplasms chemically induced, Liver Neoplasms pathology, Liver Regeneration genetics, Liver Regeneration physiology, Macrophages metabolism, Male, Membrane Glycoproteins metabolism, Mice, Mice, Knockout, Middle Aged, Oxidative Stress, Protective Factors, RNA metabolism, Reactive Oxygen Species metabolism, Receptors, Immunologic metabolism, Spheroids, Cellular, Up-Regulation, Wnt Proteins metabolism, Wnt Signaling Pathway, Wnt3 Protein metabolism, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular metabolism, Liver Neoplasms genetics, Liver Neoplasms metabolism, Membrane Glycoproteins genetics, Receptors, Immunologic genetics
- 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2021
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