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 Apc/Sigirr mice. Importantly, elevated colonic tumorigenesis in Apc/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 Apc/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 Apc/Sigirr mice. Epithelium specific re-expression of SIGIRR in Apc/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. Author details Unit of Immune Signaling and Regulation, Institut Pasteur of Shanghai, Shanghai 200025, PR China. Department of Immunology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. Division of Gastroenterology, University of British Columbia and BC Children’s Hospital, Vancouver, BC V6T 1Z4, Canada.