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Toll-Like Receptors are critical in controlling colonic inflammation and cancer

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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Correspondence to Hui Xiao.

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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 (, 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).

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