Scientific Abstract

Several studies have indicated that dysregulated host/enteric bacterial interactions are required for the development of chronic colitis. Both the colonic epithelial cells (CECs) that form a barrier between the luminal contents (including microorganisms and other antigens) and the underlying immune cells play an important role in the immunoregulation of host/microbial interactions. In fact, CECs actively participate in the induction of both innate and adaptive immune responses to the enteric microorganisms’ contents by inducing several specific molecules. These inducible molecular pathways have not, however, been fully defined. 

 

Recently, we have identified a novel, intestinal inflammation-associated inducible molecule, Chitinase 3-like-1 (CHI3L1, also known as YKL-40), which is produced by CECs and macrophages. We have used both molecular and functional analyses to demonstrate an unexpected role for CHI3L1 in enhancing bacterial adhesion and invasion on/into CECs. CHI3L1 is characterized by a strong binding affinity to chitin, a polymer of N-acetylglucosamine (GlcNAc), without enzymatic activity to degrade chitin. CHI3L1 is not synthesized by healthy individuals, but a significantly increased level of CHI3L1 is observed in the serum of patients with IBD as well as colon cancer.

 

Although the biological function of CHI3L1 in colon cancer is not known, it has been suggested that CHI3L1 may play a pivotal role in the proliferation of malignant tumors, prevent cancer cells from undergoing apoptosis, facilitate angiogenesis, impact extracellular tissue remodeling, and stimulate fibroblasts surrounding the tumor. High preoperative serum levels of CHI3L1 in patients with colon cancer were also a strong prognostic factor for a short recurrence-free interval and short overall survival. However, in vivo evidence of these hypotheses has not been found completely. The major goal of this study is to define the role of CHI3L1 in the pathogenesis of colitis-associated carcinogenic change in CECs. Our working hypothesis is that a CHI3L1-mediated signaling pathway contributes to exacerbate the chronic inflammation and initiate the formation of the inflammation-associated carcinogenesis process in CECs by 1) enhancing translocation of luminal bacteria in CECs, which may promote the formation of a precancerous stage including dysplasia, 2) activating and perpetuating a Wnt/β-catenine signaling pathway, and 3) associating with cancer-migration and proliferation as “tumor-initiating cells (stem-like cells)” in colonic mucosa. These studies will help clarify the critical role of CHI3L1 in chronic inflammation and the following colitis-associated carcinogenesis in CECs and will provide a rationale for the development of novel anti-CHI3L1 or pan-chitinase inhibitor-based immunotherapy for improving the live of patients with IBD in the near future.