PDF(Pubmed)
Abstract：
Tumor-associated macrophages play a crucial role in the tumor microenvironment. Tripartite motif 59 (TRIM59), a member of the tripartite motif (TRIM) family, is known to be associated with immunological diseases and macrophage activation. The functional and molecular mechanisms by which TRIM59 affects the occurrence and development of colorectal cancer (CRC) through macrophages are still not well understood. To address this, we generated macrophage-specific TRIM59 conditional knockout mice and utilized these mice to establish colitis-associated cancer and MC38 transplanted CRC models for further investigation. We found that the deficiency of TRIM59 in macrophages inhibited colorectal tumorigenesis in mice. This tumor-suppressive effect was achieved by promoting the activation of M1 macrophages via STAT1 signaling pathway. Further mechanistic studies revealed that TRIM59 could regulate macrophage polarization by ubiquitinating and degrading STAT1. These findings provide evidence that TRIM59 deficiency promotes M1 macrophage activation and inhibits CRC through the STAT1 signaling pathway, suggesting that the TRIM59/STAT1 signaling pathway may be a promising target for CRC.
摘要：
肿瘤相关巨噬细胞在肿瘤微环境中起着至关重要的作用。三方主题59(TRIM59)，三方主题（TRIM）家族的成员，已知与免疫性疾病和巨噬细胞活化有关。TRIM59通过巨噬细胞影响结直肠癌（CRC）发生发展的功能和分子机制尚不清楚。为了解决这个问题，我们产生了巨噬细胞特异性TRIM59条件性基因敲除小鼠,并利用这些小鼠建立结肠炎相关癌症和MC38移植CRC模型进行进一步研究.我们发现巨噬细胞中TRIM59的缺乏抑制小鼠结直肠肿瘤发生。这种肿瘤抑制作用是通过STAT1信号通路促进M1巨噬细胞的活化来实现的。进一步的机制研究表明，TRIM59可以通过泛素化和降解STAT1来调节巨噬细胞极化。这些发现提供了证据，表明TRIM59缺乏促进M1巨噬细胞活化，并通过STAT1信号通路抑制CRC，提示TRIM59/STAT1信号通路可能是CRC的一个有希望的靶点。
