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Toll-Like Receptors are critical in controlling colonic inflammation and cancer
BMC Proceedings volume 5, Article number: P87 (2011)
Despite the presence of large number and diverse populations of commensal microbes, gut mucosa has evolved to maintain “microbial-tolerance”, which is critically regulated by well-controlled Toll-like receptor (TLR) signaling. Deregulated TLR signaling has been linked to the pathogenesis of inflammatory bowel disease and colon cancer; however, the underlying mechanisms need to be further defined. In this study, we uncovered that lack of SIGIRR, a negative regulator for TLR and IL-1R signaling, led to increased genetic instability and LOH of Apc, resulting in spontaneous colonic polyposis in Apcmin/+/Sigirr-/- mice. Importantly, elevated colonic tumorigenesis in Apcmin/+/Sigirr-/- mice is dependent on the presence of commensal microbes in gut, implicating a critical role for TLR signaling in tumorigenesis. Furthermore, we demonstrated that SIGIRR-modulated TLR-mediated tumor initiation is mainly through the activation of the Akt-mTOR axis, which promotes cell cycle progression through its impact on posttranscriptional control of the key cell cycle regulators (Cyclins, c-Myc and cdk2). Moreover, abrogation of mTOR pathway by rapamycin prevented microadenoma and polyps formation in Apcmin/+/Sigirr-/- mice, providing new insights into treating human cancers. In addition, augmented production of proinflammatory cytokines, such as IL-6 and IL-23, further promoted tumor growth in Apcmin/+/Sigirr-/- mice. Epithelium specific re-expression of SIGIRR in Apcmin/+/Sigirr-/- mice ameliorated intestinal tumorigenesis. In summary, this study indicates that SIGIRR is a critical tumor suppressor that controls tumorigenesis by inhibiting TLR-induced mTOR and NFkB pathways in colonic epithelium.
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This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Xiao, H., Yin, W., Khan, M.A. et al. Toll-Like Receptors are critical in controlling colonic inflammation and cancer. BMC Proc 5 (Suppl 1), P87 (2011). https://doi.org/10.1186/1753-6561-5-S1-P87
- Inflammatory Bowel Disease
- mTOR Pathway
- Promote Tumor Growth
- Colonic Inflammation
- NFkB Pathway