Chronic inflammation has been associated with the development of malignancy since antiquity. For example, patients with inflammatory bowel disease (IBD), a chronic inflammatory disease of the intestines, manifest as much as a six-fold increased risk of colorectal cancer over their lifetime compared to the general population. Importantly, the pathogenesis of these colitis-associated cancers is poorly understood, but appears to be distinct from sporadic colorectal cancers that occur in the general population. TNF-alpha induced protein 3 (TNFAIP3), also known as A20, is a ubiquitin editing enzyme that is a well-known inhibitor of inflammation, particularly downstream of TNF-alpha signaling. Genome-wide association studies have strongly linked A20 to multiple inflammatory and autoimmune diseases such as IBD. Mice deficient in A20 develop rapidly lethal severe systemic inflammation in multiple tissues including the colon. Similarly, patients with a rare loss-of-function mutation in A20 develop early-onset autoinflammatory disease. In addition to a clear role in inflammatory disease, somatic mutations in A20 have been found in multiple types of cancer suggesting this protein also serves as a tumor suppressor. Indeed, our previous work demonstrated that A20 might play a direct role in regulating wnt/beta-catenin signaling. This pathway is known to be critically important in the pathogenesis of sporadic colon cancers. Based on these data, we hypothesize that A20 may be an important regulator of inflammation associated cancers particularly in the colon. In this application, we propose to study the effect of intestinal-epithelial cell specific deficiency of A20 in a classical murine model of colitis-associated cancer. In this system, mice are injected with a single dose of a genotoxin, azoxymethane (AOM), followed repeated induction of colitis using an epithelial irritant, dextran sodium sulfate (DSS). We hypothesize that mice with intestinal epithelial cell-specific deletion of A20 will develop larger and more numerous tumors than wild-type mice exposed to AOM-DSS. We further propose to examine gene expression changes in vitro using cell lines and murine intestinal organoids deficient in A20 after stimulation with pro-inflammatory and pro-carcinogenic cytokines. These studies will help elucidate the specific transcriptional networks and pathways affected by A20 disruption under these conditions. Our ultimate goal is to better understand the underlying pathophysiology of colitis-associated cancers and potentially provide novel therapeutic targets for this distinct clinical entity.
Chronic inflammation has long been identified as a risk factor for developing cancer. Our proposal aims to uncover the underlying mechanisms for this phenomenon. This knowledge may help us to develop more specific therapies for this distinct clinical entity.
