Organ‐specific profiles of genetic changes in cancers caused by activation‐induced cytidine deaminase expression

• Published in: International journal of cancer 2008-12, Vol.123 (12), p.2735-2740
• Main Authors: Morisawa, Toshiyuki, Marusawa, Hiroyuki, Ueda, Yoshihide, Iwai, Akio, Okazaki, Il‐mi, Honjo, Tasuku, Chiba, Tsutomu
• Format: Article
• Language: English
• Subjects: AID; alpha-Fetoproteins - genetics; alpha-Fetoproteins - metabolism; Animal tumors. Experimental tumors; Animals; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; Enzyme Activation; Experimental tumors, general aspects; gastric cancer; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Genes, myc; Genes, ras; hepatocellular carcinoma; Insulin-Like Growth Factor II - genetics; Insulin-Like Growth Factor II - metabolism; Liver Neoplasms, Experimental - enzymology; Liver Neoplasms, Experimental - genetics; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Matrix Metalloproteinase 7 - genetics; Matrix Metalloproteinase 7 - metabolism; Medical sciences; Mice; Mice, Transgenic; Mutation; Neoplasms, Experimental - enzymology; Neoplasms, Experimental - genetics; Organ Specificity; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stomach Neoplasms - enzymology; Stomach Neoplasms - genetics; transgenic mouse; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Up-Regulation
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.23853

Various molecular changes characterizing organ‐specific carcinogenesis have been identified in human tumors; however, the molecular mechanisms of the genomic changes specific for each cancer are not well defined. A transgenic (Tg) mouse model with constitutive expression of the nucleotide‐editing enzyme, activation‐induced cytidine deaminase (AID), develops tumors in various organs as a result of the mutagenic activities of AID. This phenotypic character of AID Tg mice allowed us to analyze the organ‐specific genetic changes in tumor‐related genes commonly triggered by AID‐mediated mutagenesis. Among the 80 AID Tg mice analyzed, 11 mice developed hepatocellular carcinomas, and 7 developed lung cancers. In addition, 1 developed the gastric cancer and 3 developed gastric adenomas. Organ‐specific preferences for nucleotide changes were observed in some of the tumor‐related genes in each epithelial tissue of the AID Tg mice. Of note, the c‐myc and K‐ras genes were the preferential targets of the mutagenic activity of AID in lung and stomach cancers, respectively, whereas mutations in the p53 and β‐catenin genes were commonly observed in all 3 organs. Quantitative RT‐PCR analyses revealed that alpha‐fetoprotein, insulin‐like growth factor2 and cyclin D1 genes were specifically upregulated in HCC, whereas upregulation of the matrix metalloproteinase7 gene was more marked in lung cancer. Our findings suggest that AID, a DNA mutator that plays a critical role linking inflammation to human cancers, might be involved in the generation of organ‐specific genetic diversity in oncogenic pathways during cancer development. © 2008 Wiley‐Liss, Inc.