title: Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations.
abstract: Pancreatic ductal adenocarcinoma (PDAC) develops via an accumulation of various gene mutations. The mechanism underlying the mutations in PDAC development, however, is not fully understood. Recent insight into the close association between the mutation pattern of various cancers and specific mutagens led us to investigate the possible involvement of activation-induced cytidine deaminase (AID), a DNA editing enzyme, in pancreatic tumorigenesis. Our immunohistochemical findings revealed AID protein expression in human acinar ductal metaplasia, pancreatic intraepithelial neoplasia, and PDAC. Both the amount and intensity of the AID protein expression increased with the progression from precancerous to cancerous lesions in human PDAC tissues. To further assess the significance of ectopic epithelial AID expression in pancreatic tumorigenesis, we analyzed the phenotype of AID transgenic (AID Tg) mice. Consistent with our hypothesis that AID is involved in the mechanism of the mutations underlying pancreatic tumorigenesis, we found precancerous lesions developing in the pancreas of AID Tg mice. Using deep sequencing, we also detected Kras and c-Myc mutations in our analysis of the whole pancreas of AID Tg mice. In addition, Sanger sequencing confirmed the presence of Kras, c-Myc, and Smad4 mutations, with the typical mutational footprint of AID in precancerous lesions in AID Tg mice separated by laser capture microdissection. Taken together, our findings suggest that AID contributes to the development of pancreatic precancerous lesions by inducing tumor-related gene mutations. Our new mouse model without intentional manipulation of specific tumor-related genes provides a powerful system for analyzing the mutations involved in PDAC.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Sawai
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. kodamayu@kuhp.kyoto-u.ac.jp.
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Kodama
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ota
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Maruno
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Eso
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kurita
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Shiokawa
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tsuji
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Uza
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Masui
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Marusawa
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D010179:Pancreas / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics*; D011230:Precancerous Conditions / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D017422:Sequence Analysis, DNA; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins