Project Summary
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.