296: IL-17-signaling in LGR5-positive stem cells promotes colon tumorigenesis

The colon epithelium undergoes constant self-renewal in order to maintain its function as a nutrient sensor and a physical barrier from the commensal microbiota. Colon epithelium homeostasis is altered by inflammation and tissue injury/repair. In excess of which, contributes to the development of colon cancer. Here, we investigated the impact of IL-17A on the colon epithelium homeostasis and tumor development. IL-17A signals through a heterodimeric receptor complex composed of IL-17RA and IL-17RC. We found that the colon epithelium from IL-17RC-deficient mice displayed reduced proliferation, increased cell apoptosis and increased permeability after DSS challenge compared to control mice. Moreover, the IL-17RC-deficient mice developed significantly fewer colonic tumors compared to control mice in the AOM/DSS model of colitis-associated cancer. We then aimed to identify the cell-type responsible for IL-17A-mediated impact on homeostasis and tumorigenesis. Presumably, this IL-17-responsive cell population would sustain the initial mutation induced by carcinogen AOM, self replicate, and ultimately give rise to the neoplastic foci. Since the renewal of the colon epithelium relies upon a stem-cell niche (LGR5-positive cells) at the base of each crypt, we specifically ablated IL-17 signaling by deleting the IL-17R adaptor protein Act1 from this compartment. Following the AOM/DSS regimen the Act1 CSC-KO mice developed significantly fewer colonic tumors compared to littermates. Mechanistically, IL-17A induced the activation of ERK5, ERK1/2 and JNK in colon epithelial cells. The activation of ERK5 and ERK1/2 were diminished in colon tissues of IL-17RC-deficient mice compared to that in the control mice with or without DSS treatment, implicating these MAPKs in IL-17R-dependent colon epithelium homeostasis. Furthermore, this pathway relied upon IL-17RC-dependent Act1 recruitment of TRAF4. We propose that IL-17R-Act1-TRAF4 cascade activates MAPKs in the LGR5-positive stem cells to promote regeneration after injury, consequently contributing to colon tumorigenesis by sustaining stem cells harboring a critical genetic lesion.