Downregulation of the Deiminase PADI2 Is an Early Event in Colorectal Carcinogenesis and Indicates Poor Prognosis.
Peptidyl arginine deiminases (PADI) are a family of enzymes that catalyze the poorly understood posttranslational 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 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 upregulated 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.



Downregulation of PADI2 is an early event in the pathogenesis of colorectal cancer associated with poor prognosis and points toward a possible role of citrullination in modulating tumor cells and their microenvironment. Mol Cancer Res; 14(9); 841-8. ©2016 AACR.
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Spain.
Neus
N
Cantariño
Department of Pathology, Hospital Universitari Germans Trias i Pujol (HGTP), Campus Can Ruti, Badalona, Spain.
Eva
E
Musulén
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Spain. Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Germans Trias i Pujol, Campus Can Ruti, Badalona, Spain.
Vanesa
V
Valero
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Spain.
Miquel Angel
MA
Peinado
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Spain.
Manuel
M
Perucho
Cancer Prevention and Control Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL) and CIBERESP, Barcelona, Spain. Department of Clinical Sciences, Faculty of Medicine, University of Barcelona (UB), Barcelona, Spain.
Victor
V
Moreno
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Spain.
Sònia-Vanina
SV
Forcales
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Spain. Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Germans Trias i Pujol, Campus Can Ruti, Badalona, Spain.
Julien
J
Douet
Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Spain. Josep Carreras Leukaemia Research Institute (IJC), Campus ICO-Germans Trias i Pujol, Campus Can Ruti, Badalona, Spain. mbuschbeck@carrerasresearch.org.
Marcus
M
Buschbeck
D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D063646:Carcinogenesis; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D003093:Colitis, Ulcerative / Q000201:enzymology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation; D020895:Enterocytes / Q000201:enzymology / Q000473:pathology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D006867:Hydrolases / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000201:enzymology / Q000473:pathology; D011379:Prognosis; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases
D014408:Biomarkers, Tumor; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases