Tissue Transglutaminase II Is a Key Enzyme Involved in Epithelial Regeneration and Carcinogenesis in the Setting of Ulcerative Colitis
DT Patil, C Deshpande, J Liao, MS Rao, GY Yang. Northwestern University Feinberg School of Medicine, Chicago, IL
Background: Tissue transglutaminase II (TG2) is a unique member of transglutaminase family of enzymes that catalyze calcium-dependent posttranslational modification as well as calcium-independent activities such as hydrolysis of GTP/ATP and protein disulfide isomerase reaction. TG2 overexpression has been observed in melanoma, breast and pancreatic cancer where it contributes to cancer cell adhesion, invasion and development of chemoresistance. In this study we evaluated immunohistochemical expression of TG2 in ulcerative colitis (UC) in both humans and animal model, and UC associated dysplasia and carcinoma in humans.
Design: Colectomy specimens (n=24) with active UC, 10 cases of dysplasia (8-low grade and 2 high grade) and 13 cases of carcinoma arising in the setting of UC were used in this study. Immunohistochemical expression of TG2 was scored on a semiquantitative scale based on intensity and percentage positive cells, using appropriate controls. Dextran sulfate sodium (DSS) induced UC in mice and intestinal epithelial cell line IE6 were used to test the effect of prostaglandin E2 (PGE2) and COX-2 inhibitor, celecoxib, on TG2.
Results: Low cytoplasmic expression of TG2, predominantly localized to the regenerating epithelium adjacent to ulcers and subepithelial stromal cells, was noted in 20/24(83%) cases. Low and high grade dysplastic lesions either showed no or very low expression of TG2. In contrast, 7/13 (54%) carcinomas showed significantly high level of TG2 expression compared to regenerating/dysplastic epithelium (p=0.02). TG2 expression was also noted in regenerating epithelium in DSS induced UC in mice. Large ulcers induced by celecoxib showed decreased TG2 expression in regenerating epithelium. Using western blot approach, we found that with PGE2 treatment, IE6 cell line showed dose and time dependent induction of TG2.
Conclusions: Our findings show differential strong expression of TG2 in UC-associated carcinoma, suggesting that TG2 serves as a useful marker to differentiate carcinoma from reactive and dysplastic changes. Lack of TG2 in dysplasia indicates that overexpression of this protein is a late event in UC-associated carcinogenesis. Animal model further confirms this observation and identifies PGE2 as a regulator of TG2 expression.(Partly supported by NIH CA104741).
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 66, Wednesday Morning