Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis.
Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis.
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DOI：
10.1158/0008-5472.can-13-1677
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发表时间：
2014-01-15
期刊：
影响因子：
11.2
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Morales C;Rachidi S;Hong F;Sun S;Ouyang X;Wallace C;Zhang Y;Garret-Mayer E;Wu J;Liu B;Li Z
巨噬细胞是炎症相关结肠癌发展的重要驱动因素，但其贡献的机制基础尚未完全了解。此外，Toll样受体（TLR）与结肠癌有关，但其相关的细胞作用位点尚不清楚。在这项研究中，我们表明，内质网伴侣蛋白gp 96是必不可少的肿瘤相关巨噬细胞（TAM）许可证的贡献，炎症性结肠肿瘤的发生。以巨噬细胞特异性方式基因缺失gp 96的小鼠表现出结肠炎和炎症相关结肠肿瘤发生减少。这些小鼠中结肠癌的减毒与β-连环蛋白突变率的降低、DNA修复机制效率的提高和促炎细胞因子（包括肿瘤微环境中的IL-17和IL-23）表达的降低显著相关。TAM相关炎症的遗传毒性性质通过DNA修复途径中基因表达的增加而明显。我们的工作加深了对TAM如何通过改变上皮细胞内的分子致癌程序来促进肿瘤发生的理解，并将gp 96鉴定为TAM中所需的关键伴侣蛋白，以许可其功能并影响结肠肿瘤发生中关键炎性细胞因子的表达。
Macrophages are important drivers in the development of inflammation-associated colon cancers, but the mechanistic underpinnings for their contributions are not fully understood. Further, Toll-like receptors (TLR) have been implicated in colon cancer, but their relevant cellular sites of action are obscure. In this study, we show that the endoplasmic reticulum chaperone gp96 is essential in tumor-associated macrophages (TAM) to license their contributions to inflammatory colon tumorigenesis. Mice where gp96 was genetically deleted in a macrophage-specific manner exhibited reduced colitis and inflammation-associated colon tumorigenesis. Attenuation of colon cancer in these mice correlated strikingly with reduced mutation rates of β-catenin, increased efficiency of the DNA repair machinery and reduced expression of pro-inflammatory cytokines, including IL-17 and IL-23 in the tumor microenvironment. The genotoxic nature of TAM-associated inflammation was evident by increased expression of genes in the DNA repair pathway. Our work deepens understanding of how TAM promote oncogenesis by altering the molecular oncogenic program within epithelial cells, and it identifies gp96 as a lynchpin chaperone needed in TAM to license their function and impact on expression of critical inflammatory cytokines in colon tumorigenesis.