Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression.
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 beta-catenin genes were commonly observed in all 3 organs. Quantitative RT-PCR analyses revealed that alpha-fetoprotein, insulin-like growth factor-2 and cyclin D1 genes were specifically upregulated in HCC, whereas upregulation of the matrix metalloproteinase-7 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.
Morisawa
Toshiyuki
T
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Marusawa
Hiroyuki
H
Ueda
Yoshihide
Y
Iwai
Akio
A
Okazaki
Il-mi
IM
Honjo
Tasuku
T
Chiba
Tsutomu
T
D000818:Animals; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D011905:Genes, ras; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics*; D009928:Organ Specificity; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000201:enzymology / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000509:alpha-Fetoproteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; D000509:alpha-Fetoproteins; D051176:beta Catenin; D019938:Cyclin D1; D007335:Insulin-Like Growth Factor II; D020783:Matrix Metalloproteinase 7; D003564:Cytidine Deaminase