AIM2 Inhibits Intestinal Stem Cell Proliferation in Colorectal Cancer

The cytosolic double-stranded DNA receptor absent in melanoma 2 (AIM2) assists in host defense against bacterial and viral pathogens in a manner that is dependent on inflammasome complex assembly and inflammatory cytokine release. AIM2 mutations have been identified in colorectal tumors, and defective AIM2 expression correlates with higher mortality in patients with colorectal cancer; however, the mechanisms by which AIM2 loss contributes to tumorigenesis remain unclear. Man and colleagues found that AIM2-deficient (Aim2^−/−) mice were more susceptible to colonic tumorigenesis via a mechanism that was independent of inflammasomes and many inflammatory mediators. Compared with wild-type mice, Aim2^−/− mice developed increased colonic hyperplasia and greater numbers and size of colon tumors in a mouse model of colitis-associated colorectal cancer. In addition, Aim2^−/− mice exhibited a higher number of proliferative cells per colonic crypt, elevations in phosphorylated AKT, increased expression of the proto-oncogene c-MYC and other genes encoding proteins involved in proliferation, and decreased apoptosis. Colonic epithelial stem cells from Aim2^−/− mice consistently exhibited an increased capacity to proliferate, including increased activity of cancer stem cells in response to aberrant WNT signaling, suggesting that AIM2 suppresses colorectal tumorigenesis by inhibiting the expansion of tumor-initiating intestinal stem cells. Furthermore, gene sequencing analyses revealed distinct differences in the intestinal microbiota in separately housed wild-type and Aim2^−/− mice. Co-housing with wild-type mice resulted in a reduction in the number and incidence of colon tumors in Aim2^−/− mice, suggesting that transmission of gut microbiota partially mitigates the impact of AIM2 deficiency on tumor development. Overall, this study identifies a role for the DNA receptor AIM2 and its synergy with intestinal microbiota in the protection against colorectal cancer and suggests modulation of AIM2 expression as a potential strategy to decrease colorectal cancer risk.

Man SM, Zhu Q, Zhu L, Liu Z, Karki R, Malik A, et al. Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell 2015 Jun 18 [Epub ahead of print].