Toll‐like receptor 4 regulates spontaneous intestinal tumorigenesis by up‐regulating IL‐6 and GM‐CSF
Toll‐like receptor 4 regulates spontaneous intestinal tumorigenesis by up‐regulating IL‐6 and GM‐CSF
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Toll-样受体 4 通过上调 IL-6 和 GM-CSF 调节自发性肠道肿瘤发生
DOI：
10.1111/jcmm.14742
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发表时间：
2020
影响因子：
5.3
通讯作者：
Hao Wang
中科院分区：
文献类型：
--
作者：
Yun‐Jie Shi;Quan‐Quan Zhao;Xiao‐Shuang Liu;Su‐He Dong;Ji‐Fu E;Xu Li;Cong Liu;Hao Wang
炎症是肠道肿瘤发生的重要组成部分. Toll样受体4（TLR 4）信号的激活促进了小鼠结肠炎的炎症，但TLR 4在肠道肿瘤发生中的作用尚不清楚。约80%~ 90%的结直肠肿瘤中存在大肠腺瘤性息肉病（Adenomatous Polyposis Coli，Apc）抑癌基因的失活突变，家族性腺瘤性息肉病（FAP）的肠腺瘤癌变也与Apc的胚系突变密切相关。ApcMin/+（多发性肠肿瘤）模型小鼠是FAP（一种遗传性肠癌）的良好利用模型。在这项研究中，在TLR 4充足和TLR 4缺乏的背景下产生ApcMin/+肠腺瘤小鼠，通过比较ApcMin/+WT和ApcMin/+ TLR 4 −/−小鼠的小鼠存活率、外周血细胞、骨髓造血前体细胞和肠道息肉数量，研究TLR 4在小鼠肠道中的致癌作用。结果表明，TLR 4在促进自发性肠道肿瘤发生中具有关键作用。通过高通量RNA-Seq方法筛选出显著差异基因。将这些结果与KEGG富集数据相结合后，确定TLR 4可能通过激活细胞因子-细胞因子受体相互作用和癌症信号传导途径中的途径来促进肠道肿瘤发生。在对相关基因进行一系列验证实验后，发现与ApcMin/+WT小鼠相比，ApcMin/+ TLR 4 −/−小鼠肠道肿瘤中的IL 6、GM-CSF（CSF 2）、IL 11、CCL 3、S100 A8和S100 A9显著降低。在核心下调因子的功能研究中发现，IL 6、GM-CSF、IL 11、CCL 3和S100 A8/9可以增加结肠癌细胞系的活力，降低照射和化学处理后结肠癌细胞的凋亡率。
Inflammation is as an important component of intestinal tumorigenesis. The activation of Toll‐like receptor 4 (TLR4) signalling promotes inflammation in colitis of mice, but the role of TLR4 in intestinal tumorigenesis is not yet clear. About 80%–90% of colorectal tumours contain inactivating mutations in the adenomatous polyposis coli (Apc) tumour suppressor, and intestinal adenoma carcinogenesis in familial adenomatous polyposis (FAP) is also closely related to the germline mutations in Apc. The ApcMin/+(multiple intestinal neoplasia) model mouse is a well‐utilized model of FAP, an inherited form of intestinal cancer. In this study, ApcMin/+intestinal adenoma mice were generated on TLR4‐sufficient and TLR4‐deficient backgrounds to investigate the carcinogenic effect of TLR4 in mouse gut by comparing mice survival, peripheral blood cells, bone marrow haematopoietic precursor cells and numbers of polyps in the guts of ApcMin/+WT and ApcMin/+TLR4−/−mice. The results revealed that TLR4 had a critical role in promoting spontaneous intestinal tumorigenesis. Significant differential genes were screened out by the high‐throughput RNA‐Seq method. After combining these results with KEGG enrichment data, it was determined that TLR4 might promote intestinal tumorigenesis by activating cytokine‐cytokine receptor interaction and pathways in cancer signalling pathways. After a series of validation experiments for the concerned genes, it was found that IL6, GM‐CSF (CSF2), IL11, CCL3, S100A8 and S100A9 were significantly decreased in gut tumours of ApcMin/+TLR4−/−mice compared with ApcMin/+WT mice. In the functional study of core down‐regulation factors, it was found that IL6, GM‐CSF, IL11, CCL3 and S100A8/9 increased the viability of colon cancer cell lines and decreased the apoptosis rate of colon cancer cells with irradiation and chemical treatment.