| First Author | Liu T | Year | 2024 |
| Journal | Int J Biol Sci | Volume | 20 |
| Issue | 15 | Pages | 6114-6129 |
| PubMed ID | 39664586 | Mgi Jnum | J:359446 |
| Mgi Id | MGI:7787595 | Doi | 10.7150/ijbs.98529 |
| Citation | Liu T, et al. (2024) Smad4 Deficiency in S100A4(+) Macrophages Enhances Colitis-associated Tumorigenesis by Promoting Macrophage Lipid Metabolism Augmented M2 Polarization. Int J Biol Sci 20(15):6114-6129 |
| abstractText | S100A4 is primarily expressed in intestinal macrophages, and promotes colonic inflammation and colitis-associated colon tumorigenesis. Smad4 is also expressed in the colon; however, it inhibits colitis-associated cancer (CAC) development. The specific role of Smad4 in S100A4(+) cells in CAC remains unknown. In this study, an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CAC model was established in mice with S100A4(+) cell-specific Smad4 deletion (S100A4 (Smad4-/-)). Smad4 deficiency in S100A4(+) cells exacerbated DSS-induced colitis and promoted colorectal tumorigenesis. In addition, S100A4(+) cell-specific Smad4 ablation promoted the M2 polarization of macrophages in CAC. Mechanistically, Smad4 depletion in macrophages enhanced lipid metabolism by activating the FA binding protein 2 (Fabp2)/STAT6 pathway. Furthermore, Smad4 deficiency in macrophages promoted MC38 tumor growth in myeloid-specific Smad4 deficient (Lyz (Smad4-/-)) mice, whereas blocking Fabp2 expression reversed the tumor growth. Additionally, high Smad4 expression was associated with prolonged survival in patients with colorectal cancer. Thus, Smad4 in S100A4(+) macrophages plays a tumor-inhibiting role in CAC development and supports its use as a prognostic marker in CRC patients. |
