Peptidyl arginine deiminases (PADIs) are a family of enzymes that catalyze the poorly understood post-translational modification converting arginine residues into citrullines. In this study, the role of PADIs in the pathogenesis of colorectal cancer was investigated. Specifically, RNA expression was analyzed and its association with survival in a cohort of 98 colorectal cancer patient specimens with matched adjacent mucosa and 50 controls from donors without cancer. Key results were validated in an independent collection of tumors with matched adjacent mucosa and by mining of a publicly available expression data set. Protein expression was analyzed by immunoblotting for cell lines or immunohistochemistry (IHC) for patient specimens that further included 24 cases of adenocarcinoma with adjacent dysplasia and 11 cases of active ulcerative colitis. The data indicate that PADI2 is the dominantly expressed PADI enzyme in colon mucosa and is up-regulated during differentiation. PADI2 expression is low or absent in colorectal cancer. Frequently this occurs already at the stage of low-grade dysplasia. Mucosal PADI2 expression is also low in ulcerative colitis. The expression level of PADI2 in tumor and adjacent mucosa correlates with differential survival: low levels associate with poor prognosis. Implications: Downregulation of PADI2 is an early event in the pathogenesis of colorectal cancer associated with poor prognosis and points towards a possible role of citrullination in modulating tumor cells and their microenvironment.
- Received January 28, 2016.
- Revision received April 25, 2016.
- Accepted May 23, 2016.
- Copyright ©2016, American Association for Cancer Research.