Intestinal epithelium-derived BATF3 promotes colitis-associated colon cancer through facilitating CXCL5-mediated neutrophils recruitment
Intestinal epithelium-derived BATF3 promotes colitis-associated colon cancer through facilitating CXCL5-mediated neutrophils recruitment
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肠上皮来源的 BATF3 通过促进 CXCL5 介导的中性粒细胞募集促进结肠炎相关结肠癌
DOI：
10.1038/s41385-020-0297-3
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发表时间：
2020-05-28
影响因子：
8
通讯作者：
Deng, H. X.
中科院分区：
文献类型：
--
作者：
Lin, Y.;Cheng, L.;Deng, H. X.
摘要炎症是结肠癌发生发展的关键因素。碱性亮氨酸拉链转录因子ATF-like 3（basic leucine zipper transcription factor ATF-like 3，BATF 3）通过调节1型树突状细胞（type 1 dendritic cells，cDC 1 s）的发育，在感染和肿瘤免疫中发挥重要作用。然而，BATF 3在结肠炎和结肠炎相关结肠癌（CAC）中的功能仍不清楚。在此，使用BATF 3野生型和敲除小鼠构建AOM/DSS诱导的CAC模型。此外，还采用DSS诱导的慢性结肠炎、骨髓交叉输血（BMT）、中性粒细胞敲除等动物模型进行深入研究。我们发现，肠上皮细胞中的BATF 3缺陷而不是cDC 1 s中的BATF 3缺陷抑制CAC，其依赖于炎症刺激。在机制上，BATF 3通过与JunD形成异源二聚体直接促进CXCL 5的转录，并通过CXCL 5-CXCR 2轴加速中性粒细胞的募集，最终增加CAC的发生和发展。组织芯片和TCGA数据也表明BATF 3的高表达与结直肠癌和其他炎症相关肿瘤的不良预后正相关。总之，我们的研究结果表明，肠上皮来源的BATF 3依赖于炎症刺激，以促进CAC，和BATF 3有望成为一种新的诊断指标结肠炎和CAC。
Abstract Inflammation is a critical player in the development and progression of colon cancer. Basic leucine zipper transcription factor ATF-like 3 (BATF3) plays an important role in infection and tumor immunity through regulating the development of conventional type 1 dendritic cells (cDC1s). However, the function of BATF3 in colitis and colitis-associated colon cancer (CAC) remains unclear. Here, BATF3 wild-type and knockout mice were used to construct an AOM/DSS-induced CAC model. In addition, DSS-induced chronic colitis, bone marrow cross-transfusion (BMT), neutrophil knockout, and other animal models were used for in-depth research. We found that BATF3 deficiency in intestinal epithelial cells rather than in cDC1s inhibited CAC, which was depended on inflammatory stimulation. Mechanistically, BATF3 directly promoted transcription of CXCL5 by forming a heterodimer with JunD, and accelerated the recruitment of neutrophils through the CXCL5-CXCR2 axis, ultimately increasing the occurrence and development of CAC. Tissue microarray and TCGA data also indicated that high expression of BATF3 was positively correlated with poor prognosis of colorectal cancer and other inflammation-related tumors. In summary, our results demonstrate that intestinal epithelial-derived BATF3 relies on inflammatory stimulation to promote CAC, and BATF3 is expected to be a novel diagnostic indicator for colitis and CAC.