Liu Ting, Zhang Xinyuan, Yan Xuanxuan, Cheng Leirong, Yan Xinlong, Zeng Fanxin, Li Xue, Chen Zhinan, Gu Jianchun, Zhang Jinhua
School of Life Science and Technology, Jinan University, Guangzhou, Guangdong Province, P.R. China.
The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing, P.R. China.
Int J Biol Sci. 2024 Nov 11;20(15):6114-6129. doi: 10.7150/ijbs.98529. eCollection 2024.
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 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 ) 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.
S100A4主要在肠道巨噬细胞中表达，并促进结肠炎症和结肠炎相关的结肠癌发生。Smad4也在结肠中表达；然而，它抑制结肠炎相关癌症（CAC）的发展。Smad4在CAC的S100A4细胞中的具体作用尚不清楚。在本研究中，在具有S100A4细胞特异性Smad4缺失（S100A4 ）的小鼠中建立了一种由氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）诱导的CAC模型。S100A4细胞中Smad4的缺乏加剧了DSS诱导的结肠炎并促进了结直肠癌的发生。此外，S100A4细胞特异性Smad4缺失促进了CAC中巨噬细胞的M2极化。机制上，巨噬细胞中Smad4的缺失通过激活脂肪酸结合蛋白2（Fabp2）/信号转导和转录激活因子6（STAT6）途径增强了脂质代谢。此外，巨噬细胞中Smad4的缺乏促进了髓系特异性Smad4缺陷（Lyz ）小鼠中MC38肿瘤的生长，而阻断Fabp2的表达则逆转了肿瘤的生长。此外，Smad4的高表达与结直肠癌患者的长期生存相关。因此，S100A4巨噬细胞中的Smad4在CAC发展中起肿瘤抑制作用，并支持其作为CRC患者的预后标志物。
