Thursday, July 16, 2015
Grand Hall and Gallery, Ground Floor & 1st Floor (Maritim Hotel)
Death-associated protein kinase (DAP-kinase, DAPk, or DAPK) is a well-known tumor suppressor. Diminished DAPK expression is found in various types of cancer including B lymphoma and chronic lymphocytic leukemia. We observed that DAPK mRNA was significantly down-regulated in CRC tissues compare with adjacent normal tissues in 55 colorectal patients, suggesting a strong correlation between DAPK expression and the tumorigenesis of CRC. DAPK has also been found as a positive modulator in NLRP3 inflammsome signaling, which plays a critical role in the development of colitis and colitis-associated carcinogenesis (CAC). Therefore, we sought to assess the role of DAPK in inflammation-driven colon carcinogenesis of gastrointestinal inflammation. We found that DAPK-deficient mice showed increased susceptibility to acute and recurring DSS-induced colitis. DSS treatment in DAPK-deficient mice led to a significant reduction in body weight compared with DSS-treated wild-type mice. The colon length was significantly shorter in DAPK-deficient mice than that in control mice. Furthermore, mature IL-18 was significantly decreased in DSS-treated DAPK-deficient colon homogenates. In colonic epithelial cells, over-expressing DAPK increased the IL-18 maturation by triggering inflammasome activation, while knockdown DAPK decreased the IL-18 maturation, suggesting DAPK is required for inflammasome-mediated IL-18 production in colonic epithelial cells. Based on these results, we demonstrated that DAPK may regulate IL-18 maturation through the epithelial inflammasome. Upon injury, DAPK-deficiency resulted in defective regeneration of the colonic mucosa, leading to increased intestinal inflammation and accelerated colitis-associated tumorigenesis. This finding may provide insights into the development of new therapeutic targets and approaches to treat IBD and colitis-associated CRC.