title: REG4 is associated with carcinogenesis in the 'intestinal' pathway of intraductal papillary mucinous neoplasms.
abstract: Subclassification of intraductal papillary mucinous neoplasms of the pancreas (IPMNs), based on morphological features and immunohistochemical profiles, has been proposed. Intestinal-type IPMNs frequently show moderate to severe dysplasia. Regenerating islet-derived family, member 4 (REG4) is associated with the adenoma-carcinoma sequence in colon cancer and it is also associated with intestinal phenotype. Therefore, to identify REG4 expression in IPMNs may be helpful to detect high-grade IPMNs. We also investigated REG4 expression and CDX2 expression in IPMNs. To investigate the expressions of REG4 and CDX2 in IPMNs and in invasive ductal adenocarcinoma derived from IPMN, we used immunohistochemical staining and microdissection-based quantitative real-time reverse transcription-polymerase chain reaction. Among 125 IPMNs, 43 (34%) were positive for REG4 and most of the intestinal-type IPMNs showed its expression (35/38). The positive ratio of REG4 expression in colloid carcinoma (5/7) was significantly higher than that in tubular carcinoma (1/17; P=0.003). Most of CDX2-positive cases (31/33) expressed REG4 protein, whereas only 12 of 92 CDX2-negative cases did (P<0.001). The levels of REG4 mRNA in intestinal-type IPMN were significantly higher compared to those in gastric-type IPMN or to normal pancreatic ductal epithelium (P=0.005, P=0.004, respectively). REG4 expression was observed more frequently in borderline lesions (14/28) and carcinoma (21/45) compared to adenoma (8/52). Using the Ki-67 labeling index, REG4 expression was significantly correlated with proliferative activity in borderline lesions. We conclude that REG4 is involved in the 'intestinal' pathway of carcinogenesis in IPMN.
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Nakata
authors.forename: Eishi
authors.initials: E
authors.lastname: Nagai
authors.forename: Kenoki
authors.initials: K
authors.lastname: Ohuchida
authors.forename: Shinich
authors.initials: S
authors.lastname: Aishima
authors.forename: Akifumi
authors.initials: A
authors.lastname: Hayashi
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyasaka
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Mizumoto
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
authors.forename: Masazumi
authors.initials: M
authors.lastname: Tsuneyoshi
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000378:metabolism / Q000473:pathology; D000231:Adenocarcinoma, Papillary / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis; D000071616:CDX2 Transcription Factor; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000235:genetics; D042282:Microdissection; D055262:Mucin-2 / Q000096:biosynthesis; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D000073718:Pancreatitis-Associated Proteins; D011230:Precancerous Conditions / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D037181:Lectins, C-Type; C524625:MUC2 protein, human; D055262:Mucin-2; D000073718:Pancreatitis-Associated Proteins; C428528:REG4 protein, human; D012333:RNA, Messenger