Toll‐like receptor 4 regulates spontaneous intestinal tumorigenesis by up‐regulating IL‐6 and GM‐CSF

Abstract

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.

Biological characteristics of IL-6 and related intestinal diseases

“…Corticotrophin-releasing hormone (CRH)/CRHR1 [140] KIOM-MA/MA128 [141] [herbal] Toll-like receptor 4 [142] Cocoa [143] Sonic hedgehog (SHH) signaling [144] IL-6 monoclonal antibody (mAb) [145] Probiotic agent VSL#3 [146]; Balsalazide (BSZ) [146] Based on the fact that some typical symptoms in PD like increasing colon transit time and constipation [147] resemble those in IBD, indicating the deficits in the intestinal immune barrier, and that some of them appear even earlier in the intestine than the motor ones finally manifest, researchers postulated the existence of brain-gut-axis modulation system in PD [148]. Also concerning the direction by which the disease spreads, two views exist among scholars, which are from brain to the gut or vice versa [149].…”

Development and validation of a five-immune gene prognostic risk model in colon cancer

“…KEGG analysis found that cytokine-cytokine receptor interaction, chemokine signaling pathway, and MAPK signaling pathway were significant pathways. Cytokine-cytokine receptor interaction was related to the viability of colon cancer cell lines [29]. Besides, previous studies have demonstrated that abnormally activated MAPK pathway is closely associated with growth and metastasis of colon cancer [30,31].…”

Lactation Associated Genes Revealed in Holstein Dairy Cows by Weighted Gene Co-Expression Network Analysis (WGCNA)

“…The TruSeq Stranded mRNA LT Sample Prep Kit (Illumina, RS-122-2101) was used for the construction of 18 cDNA libraries [ 24 ], and the Illumina sequencing platform (HiSeqTM 2500) was used to sequence these libraries, generating 125 bp paired-end reads [ 25 , 26 ]. Raw data underwent recognition analysis to obtain original sequencing.…”