Article ; Online: Interleukin-21 receptor signaling promotes metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma by inducing immunosuppressive IgA
2024 Volume 23, Issue 1, Page(s) 95
Abstract: Background: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed ... ...
| Abstract | Background: Dysregulation of immune surveillance is tightly linked to the development of metabolic dysfunction-associated steatohepatitis (MASH)-driven hepatocellular carcinoma (HCC); however, its underlying mechanisms remain unclear. Herein, we aimed to determine the role of interleukin-21 receptor (IL-21R) in MASH-driven HCC. Methods: The clinical significance of IL-21R was assessed in human HCC specimens using immunohistochemistry staining. Furthermore, the expression of IL-21R in mice was assessed in the STAM model. Thereafter, two different MASH-driven HCC mouse models were applied between IL-21R-deficient mice and wild type controls to explore the role of IL-21R in MASH-driven HCC. To further elucidate the potential mechanisms by which IL-21R affected MASH-driven HCC, whole transcriptome sequencing, flow cytometry and adoptive lymphocyte transfer were performed. Finally, flow cytometry, enzyme-linked immunosorbent assay, immunofluorescent staining, chromatin immunoprecipitation assay and western blotting were conducted to explore the mechanism by which IL-21R induced IgA Results: HCC patients with high IL-21R expression exhibited poor relapse-free survival, advanced TNM stage and severe steatosis. Additionally, IL-21R was demonstrated to be upregulated in mouse liver tumors. Particularly, ablation of IL-21R impeded MASH-driven hepatocarcinogenesis with dramatically reduction of lipid accumulation. Moreover, cytotoxic CD8 Conclusions: IL-21R plays a cancer-promoting role by inducing IgA |
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| MeSH term(s) | Animals ; Humans ; Male ; Mice ; B-Lymphocytes/metabolism ; B-Lymphocytes/immunology ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Carcinoma, Hepatocellular/etiology ; Carcinoma, Hepatocellular/immunology ; Carcinoma, Hepatocellular/genetics ; Cell Line, Tumor ; Disease Models, Animal ; Fatty Liver/metabolism ; Fatty Liver/pathology ; Fatty Liver/etiology ; Gene Expression Regulation, Neoplastic ; Immunoglobulin A/metabolism ; Interleukin-21 Receptor alpha Subunit/metabolism ; Interleukin-21 Receptor alpha Subunit/genetics ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Liver Neoplasms/etiology ; Liver Neoplasms/immunology ; Liver Neoplasms/genetics ; Receptors, Interleukin-21/metabolism ; Receptors, Interleukin-21/genetics ; Signal Transduction |
| Chemical Substances | IL21R protein, human ; Immunoglobulin A ; Interleukin-21 Receptor alpha Subunit ; Receptors, Interleukin-21 ; Il21r protein, mouse |
| Language | English |
| Publishing date | 2024-05-08 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2091373-4 |
| ISSN | 1476-4598 ; 1476-4598 |
| ISSN (online) | 1476-4598 |
| ISSN | 1476-4598 |
| DOI | 10.1186/s12943-024-02001-2 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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