Skip to main content
SpringerLink
Log in

A novel mechanism for inflammation-associated carcinogenesis; an important role of activation-induced cytidine deaminase (AID) in mutation induction

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Chiba T, Marusawa H, Seno H, Watanabe N (2008) Mechanism for gastric cancer development by Helicobacter pylori infection. J Gastroenterol Hepatol 23:1175–1181

    Article  CAS  PubMed  Google Scholar 

  2. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444

    Article  CAS  PubMed  Google Scholar 

  3. 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

    Article  CAS  PubMed  Google Scholar 

  4. 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

    CAS  PubMed  Google Scholar 

  5. 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

    CAS  PubMed  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. 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

    CAS  PubMed  Google Scholar 

  8. Friedberg EC, McDaniel LD, Schultz RA (2004) The role of endogenous and exogenous DNA damage and mutagenesis. Curr Opin Genet Dev 14:5–10

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  PubMed  Google Scholar 

  10. Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411:366–374

    Article  CAS  PubMed  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. Greenman C, Stephens P, Smith R et al (2007) Patterns of somatic mutation in human cacer genomes. Nature 446:153–158

    Article  CAS  PubMed  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. 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

    Article  CAS  PubMed  Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. 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

    Article  CAS  PubMed  Google Scholar 

  17. 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

    Article  CAS  PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. 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

    Article  Google Scholar 

  22. 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

    Article  CAS  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Article  CAS  PubMed  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. Bos JL (1989) Ras oncogenes in human cacer: a review. Cancer Res 49:4682–4689

    CAS  PubMed  Google Scholar 

  28. 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

    Article  CAS  PubMed  Google Scholar 

  29. 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

    Article  CAS  PubMed  Google Scholar 

  30. 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

    Google Scholar 

  31. 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

    Article  CAS  PubMed  Google Scholar 

  32. Liu M, Schatz DG (2009) Blancing AID and DNA repair during somatic hypermutation. Trends Immunol 30:173–181

    Article  CAS  PubMed  Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. 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

    Article  CAS  PubMed  Google Scholar 

  35. 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

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kawahara-cho 54, Shogoin, Sakyo, Kyoto, 606-8507, Japan

    Tsutomu Chiba & Hiroyuki Marusawa

Authors
  1. Tsutomu Chiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroyuki Marusawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tsutomu Chiba.

Additional information

Conflict of interest statement

The authors declare that they have no conflict of interests.

Rights and permissions

Reprints 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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-009-0527-3

Keywords

Search

Navigation