Abstract
Inflammation is a risk for cancer development; however, its mechanism is unknown. Recent studies have revealed that activation-induced cytidine deaminase (AID), which plays essential roles in both class-switch recombination and somatic hypermutation of immunoglobulin gene in B lymphocytes, is aberrantly expressed in non-lymphoid cells not only by H.pylori and HCV infection but also by various proinflammatory cytokines, leading to the generation of gene mutations. These findings not only suggested a new mechanism of inflammation-associated carcinogenesis but has also opened up a new field of tumor biology.



Similar content being viewed by others
References
Chiba T, Marusawa H, Seno H, Watanabe N (2008) Mechanism for gastric cancer development by Helicobacter pylori infection. J Gastroenterol Hepatol 23:1175–1181
Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444
Higashi H, Nakaya A, Tsutsumi R, Yokoyama K, Fujii Y, Ishikawa S, Higuchi M, Takahashi A, Kurashima Y, Teishikata Y, Tanaka S, Azuma T, Hatakeyama M (2004) Helicobacter pylori CagA induces Ras-independent morphogenic response through SHP2 recruitment and activation. J Biol Chem 279:17205–17216
Marusawa H, Hijikata M, Chiba T, Shimotono K (1999) Hepatitis C virus core protein inhibits Fas- and tumor necrosis facto alpha-mediated apoptosis via NF-kB activation. J Virol 73:4713–4720
Seno H, Satoh K, Tsuji S, Shiratsuchi T, Harada Y, Hamajima N, Sugano K, Kawano S, Chiba T (2007) Novel IL4 and IL1RN variations associated with non-cardia gastric cancer in Japan: Comprehensive analysis of 207 polymorphisms of 11 cytokines. J Gastroenterol Hepatol 22:729–37
Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B, Betz KS, Oesterreicher MP, Bjorkdahl O, Fox JG, Wang TC (2008) Overexpression of interleukin-1β induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14:408–419
Seno H, Oshima M, Ishikawa TO, Oshima H, Takaku K, Chiba T, Narumiya S, Taketo MM (2002) Cyclooxygenase 2 and prostaglandin E2 receptor EP2-dependent angiogenesis in Apc716mouse intestinal polyps. Cancer Res 62:506–511
Friedberg EC, McDaniel LD, Schultz RA (2004) The role of endogenous and exogenous DNA damage and mutagenesis. Curr Opin Genet Dev 14:5–10
Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Wills J, Dawson D, Willson JKV, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman E, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE (2006) The consensus coding sequences of human breat and colorectal cancers. Science 314:268–274
Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411:366–374
Cleary SP, Cotterchio M, Jenkins MA, Kim H, Bristow R, Green R, Haile R, Hopper JL, LeMarchand L, Lindor N, Parfrey P, Potter J, Younghusband B, Gallinger S (2009) Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 136:1251–1260
Greenman C, Stephens P, Smith R et al (2007) Patterns of somatic mutation in human cacer genomes. Nature 446:153–158
Muramatsu M, Sankaranand VS, Anant S, Sugai M, Kinoshita K, Davidson NO, Honjo T (1999) Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J Biol Chem 274:18470–18476
Muramatsu M, Sankaranand VS, Anant S, Sugai M, Kinoshita K, Davidson NO, Honjo T (2000) Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102:553–563
Greeve J, Philipsen A, Krause K, Klapper W, Heidorn K, Castle BE, Janda J, Marcu KB, Parwaresch R (2003) Expression of activation-induced cytidine deaminase in human B-cell non-Hodgkin lymphomas. Blood 101:3574–3580
Albesiano E, Messmer BT, Damle RN, Allen SL, Rai KR, Chiorazzini N (2003) Activation-induced cytidine deaminase in chroniclymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone. Blood 102:3333–3339
Okazaki LM, Hiai H, Kakazu N, Yamada S, Muramatsu M, Kinoshita K et al (2003) Constitutive expression of AID leads to tumorigenesis. J Exp Med 197:1173–1181
Morisawa T, Marusawa H, Ueda Y, Iwai A, Okazaki IM, Honjo T, Chiba T (2008) Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. Int J Cancer 123:2735–2740
Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, Azuma T, Okazaki IM, Honjo T, Chiba T (2007) Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 13:470–476
Endo Y, Marusawa H, Kinoshita K, Morisawa T, Sakurai T, Okazaki IM, Watashi K, Shimotono K, Honjo T, Chiba T (2007) Expression of human activation-induced cytidine deaminase in human hepatocytes via NF-kB signaling. Oncogene 26:5587–5595
Kou T, Marusawa H, Kinoshita K, Endo Y, Okazaki H, Ueda Y, Kodama Y, Haga H, Chiba T (2006) Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis. Int J Cancer 120:469–476
Kim CJ, Song JH, Cho YG, Cao Z, Kim SY, Nam SW, Lee JY, Park WS (2007) Activation-induced cytidine deaminase expression in gastric cancer. Tumor Biol 28:333–339
Komori J, Marusawa H, Machimoto T, Endo Y, Kinoshita K, Kou T, Haga H, Ikai I, Uemoto S, Chiba T (2008) Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. Hepatology 47:888–896
Endo Y, Marusawa H, Kou T, Nakase H, Fujii S, Fujimori T, Kinoshita K, Honjo T, Chiba T (2008) Activation-induced cytidine deaminase links between inflammation to colitis-associated colorectal cancers. Gastroenterology 135:889–898
Maeda S, Akanuma M, Mitsuno Y, Hirata Y, Ogura K, Yoshida H, Shiratori Y, Omata M (2001) Distinct mechanism of Helicobacter pylori-mediated NFκB activation between gastric cancer cells and monocytic cells. J Biol Chem 276:44856–44864
Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Memet S, Huerre MR, Coyle AJ, Di Stefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL (2004) Nod1 responds to peptidogllycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 5:1166–1174
Bos JL (1989) Ras oncogenes in human cacer: a review. Cancer Res 49:4682–4689
Shen HM, Poirier MG, Allen MJ, North J, Lal R, Widom J, Storb U (2009) The activation-induced cytidine deaminase (AID) efficiently targets DNA in nucleosomes but only during transcription. J Exp Med 206:1057–1071
Takai A, Toyoshima T, Uemura M, Kitawaki Y, Marusawa H, Hiai H, Yamada S, Okazaki I, Honjo T, Chiba T, Kinoshita K (2009) A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations. Oncogene 28:469–478
Liu M, Duke JL, Richter DJ, Vinuesa CG, Goodnow CC, Kleinstein SH, Schatz DG (2008) Two levels of protection for the B cell genome during somatic hypermutation. Nature 451:841–845
Wilson TM, Vaisman A, Martomo SA, Sullivan P, Lan L, Hanaoka F, Yasui A, Woodgate R, Gearhart PJ (2005) MSH2-MSH6 stimulates DNA polymerase η, suggesting a role for A:T mutations in antibody genes. J Exp Med 201:637–645
Liu M, Schatz DG (2009) Blancing AID and DNA repair during somatic hypermutation. Trends Immunol 30:173–181
Dorsett Y, Robbiani DF, Jankovic M, Reina-San- Martin B, Eisenreich TR, Nussenzweig MC (2007) A role for AID in chromosome translocations between c-myc and the IgH variable region. J Exp Med 204:2225–2232
Robbiani DF, Bothmer A, Callen E, Reina-San-Martin B, Dorsett Y, Difilippantonio S, Bolland DJ, Chen HT, Corcoran AE, Nussenzweig A, Nussenzweig MC (2008) AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell 135:1028–1038
Rai K, Huggins IJ, James SR, Karpf AR, Jones DA, Caims BR (2008) DNA demethylation in Zebrafish involves the coupling of a deaminase, a glycosylase, and Gadd45. Cell 135:1201–1212
Author information
Authors and Affiliations
Corresponding author
Additional information
Conflict of interest statement
The authors declare that they have no conflict of interests.
Rights and permissions
About this article
Cite this article
Chiba, T., Marusawa, H. A novel mechanism for inflammation-associated carcinogenesis; an important role of activation-induced cytidine deaminase (AID) in mutation induction. J Mol Med 87, 1023–1027 (2009). https://doi.org/10.1007/s00109-009-0527-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-009-0527-3