TLR4 signaling in the development of colitis-associated cancer and its possible interplay with microRNA-155

Abstract

Ulcerative colitis (UC) has closely been associated with an increased risk of colorectal cancer. However, the exact mechanisms underlying colitis-associated cancer (CAC) development remain unclear. As a classic pattern-recognition receptor, Toll like receptor (TLR)4 is a canonical receptor for lipopolysaccharide of Gram-negative bacteria (including two CAC-associated pathogens Fusobacterium nucleatum and Salmonella), and functions as a key bridge molecule linking oncogenic infection to colonic inflammatory and malignant processes. Accumulating studies verified the overexpression of TLR4 in colitis and CAC, and the over-expressed TLR4 might promote colitis-associated tumorigenesis via facilitating cell proliferation, protecting malignant cells against apoptosis, accelerating invasion and metastasis, as well as contributing to the creation of tumor-favouring cellular microenvironment. In recent years, considerable attention has been focused on the regulation of TLR4 signaling in the context of colitis-associated tumorigenesis. MicroRNA (miR)-155 and TLR4 exhibited a similar dynamic expression change during CAC development and shared similar CAC-promoting properties. The available data demonstrated an interplay between TLR4 and miR-155 in the context of different disorders or cell lines. miR-155 could augment TLR4 signaling through targeting negative regulators SOCS1 and SHIP1; and TLR4 activation would induce miR-155 expression via transcriptional and post-transcriptional mechanisms. This possible TLR4-miR-155 positive feedback loop might result in the synergistic accelerating effect of TLR4 and miR-155 on CAC development.

Gut Microbiome in Inflammatory Bowel Disease: Role in Pathogenesis, Dietary Modulation, and Colitis-Associated Colon Cancer

“…Many of these PRRs, such as TLRs, recognize pathogens from their pathogen-associated molecular patterns (PAMPS), as well as danger-associated molecular patterns (DAMPs) that come from stressed or damaged cells [ 81 , 82 ]. Signaling from TLR4 might act as a pivotal pathogen-activated tumor signal pathway in the development of CAC [ 83 , 84 ]. TLR4 binds to lipopolysaccharide (LPS) from gram-negative bacteria, such as Fusobacterium nucleatum and Salmonella [ 85 , 86 ].…”

MicroRNAs in Inflammatory Bowel Disease and Its Complications

“…Numerous studies have shown that miRNAs may significantly influence cancer tumorigenesis, proliferation, invasion, and metastasis [ 41 , 44 , 45 ]. Increased expression of TLR4 is a distinctive characteristic of CAC that co-occurs with miR-155 upregulation alongside downregulation of suppressor of cytokine signaling 1 (SOCS1) and Src homology 2 domain-containing inositol-5′-phosphatase 1 in SW480 and HCT116 cancer cells [ 42 , 46 ]. This increased activation leads to constitutive STAT3 activation.…”

“…This increased activation leads to constitutive STAT3 activation. Upregulated TLR4 signaling alongside upregulated miR-9, miR-25, miR-92a, and miR-301A may ultimately induce epithelial to mesenchymal transition (EMT) by targeting E-cadherin, a cell adhesion protein, to promote tumor invasion and metastasis [ 38 , 46 , 47 ].…”

Differential Transcriptomic Profiles Following Stimulation with Lipopolysaccharide in Intestinal Organoids from Dogs with Inflammatory Bowel Disease and Intestinal Mast Cell Tumor

“…The TLR4 signaling pathway has been shown to drive tumorigenesis and exhibit some antitumor effect on TLR4 activation [ 22 , 23 ]. TLR4 serves as a key bridge molecule linking oncogenic infection to colonic inflammatory and malignant processes by inducing miR-155 expression via transcriptional and post-transcriptional mechanisms [ 24 ]. Conversely, miR-155 can also augment TLR4 signaling by targeting negative regulators SOCS1 and SHIP1 [ 24 ].…”

“…TLR4 serves as a key bridge molecule linking oncogenic infection to colonic inflammatory and malignant processes by inducing miR-155 expression via transcriptional and post-transcriptional mechanisms [ 24 ]. Conversely, miR-155 can also augment TLR4 signaling by targeting negative regulators SOCS1 and SHIP1 [ 24 ]. Regardless of the significance of an impaired intestinal barrier indicated by elevated circulating LPS levels, the role of LPS in regulating signaling pathways involved in the development of intestinal inflammation in IBD remains mostly unknown.…”