Activation-induced cytidine deaminase contributes to pancreatic tumorigenesis by inducing tumor-related gene mutations
Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, en induisant des mutations de plusieurs gènes, une enzyme (cytidine désaminase induite par l'activation) favorise le développement d'un adénocarcinome canalaire du pancréas
Pancreatic ductal adenocarcinoma (PDA) develops via an accumulation of various gene mutations. The mechanism underlying the mutations in PDA 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 immunohistochemistry findings revealed AID protein expression in human acinar ductal metaplasia (ADM), pancreatic intraepithelial neoplasia (PanIN), and PDA. Both the amount and intensity of the AID protein expression increased with the progression from precancerous to cancerous lesions in human PDA 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 PDA.