| First Author | Xin X | Year | 2024 |
| Journal | Theranostics | Volume | 14 |
| Issue | 15 | Pages | 5853-5868 |
| PubMed ID | 39346534 | Mgi Jnum | J:354610 |
| Mgi Id | MGI:7735806 | Doi | 10.7150/thno.97276 |
| Citation | Xin X, et al. (2024) Hepatocyte-specific Smad4 deficiency inhibits hepatocarcinogenesis by promoting CXCL10/CXCR3-dependent CD8(+)- T cell-mediated anti-tumor immunity. Theranostics 14(15):5853-5868 |
| abstractText | Rationale: Sma mothers against decapentaplegic homologue 4 (Smad4) is a key mediator of the transforming growth factor beta (TGF-beta) pathway and plays complex and contradictory roles in hepatocellular carcinoma (HCC). However, the specific role of Smad4 in hepatocytes in regulating hepatocarcinogenesis remains poorly elucidated. Methods: A diethylnitrosamine/carbon tetrachloride-induced HCC model was established in mice with hepatocyte-specific Smad4 deletion (Alb(Smad4-/-)) and liver tumorigenesis was monitored. Immune cell infiltration was examined by immunofluorescence and fluorescence activated cell sorting (FACS). Cytokine secretion, glycolysis, signal pathway, and single-cell RNA sequencing were analysed for mechanism. Results: Alb(Smad4-/-) mice exhibited significantly fewer and smaller liver tumor nodules, less fibrosis, reduced myeloid-derived suppressor cell infiltration and increased CD8(+) T cell infiltration. Smad4 deletion in hepatocytes enhanced C-X-C motif ligand 10 (CXCL10) secretion, promoting tumor necrosis factor-alpha (TNF-alpha) production in CD8(+) T cells. The loss of Smad4 activated the CXCL10/mammalian target of rapamycin (mTOR)/lactate dehydrogenase A (LDHA) pathway, which increased glycolytic activity in CD8(+) T cells. HCC patients with high Smad4 expression exhibited decreased CD8(+) T cell infiltration and altered glycolysis. Conclusion: Our results demonstrate that Smad4 in hepatocytes promotes hepatocarcinogenesis and is a potential and candidate target for the prevention and therapy of HCC. |
