Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

Abstract

Activation-induced cytidine deaminase (AID), the only enzyme that is known to be able to induce mutations in the human genome, is required for somatic hypermutation and class-switch recombination in B lymphocytes. Recently, we showed that AID is implicated in the pathogenesis of human cancers including hepatitis C virus (HCV)-induced human hepatocellular carcinoma (HCC). In this study, we established a new AID transgenic mouse model (TNAP-AID) in which AID is expressed in cells producing tissue-nonspecific alkaline phosphatase (TNAP), which is a marker of primordial germ cells and immature stem cells, including ES cells. High expression of TNAP was found in the liver of the embryos and adults of TNAP-AID mice. HCC developed in 27% of these mice at the age of approximately 90 weeks. The HCC that developed in TNAP-AID mice expressed α-fetoprotein and had deleterious mutations in the tumour suppressor gene Trp53, some of which corresponded to those found in human cancer. In conclusion, TNAP-AID is a mouse model that spontaneously develops HCC, sharing genetic and phenotypic features with human HCC, which develops in the inflamed liver as a result of the accumulation of genetic changes.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Endo Y, Marusawa H, Kinoshita K, Morisawa T, Sakurai T, Okazaki IM et al. (2007). Expression of activation-induced cytidine deaminase in human hepatocytes via NF-kappaB signaling. Oncogene 26: 5587–5595.

    Article  CAS  PubMed  Google Scholar 

  • Factor VM, Kao CY, Santoni-Rugiu E, Woitach JT, Jensen MR, Thorgeirsson SS . (1997). Constitutive expression of mature transforming growth factor beta1 in the liver accelerates hepatocarcinogenesis in transgenic mice. Cancer Res 57: 2089–2095.

    CAS  PubMed  Google Scholar 

  • Fan CY, Pan J, Usuda N, Yeldandi AV, Rao MS, Reddy JK . (1998). Steatohepatitis, spontaneous peroxisome proliferation and liver tumors in mice lacking peroxisomal fatty acyl-CoA oxidase. Implications for peroxisome proliferator-activated receptor alpha natural ligand metabolism. J Biol Chem 273: 15639–15645.

    Article  CAS  PubMed  Google Scholar 

  • Honjo T, Kinoshita K, Muramatsu M . (2002). Molecular mechanism of class switch recombination: linkage with somatic hypermutation. Annu Rev Immunol 20: 165–196.

    Article  CAS  PubMed  Google Scholar 

  • Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J et al. (2004). Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113: 1774–1783.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Katzenellenbogen M, Pappo O, Barash H, Klopstock N, Mizrahi L, Olam D et al. (2006). Multiple adaptive mechanisms to chronic liver disease revealed at early stages of liver carcinogenesis in the Mdr2-knockout mice. Cancer Res 66: 4001–4010.

    Article  CAS  PubMed  Google Scholar 

  • Kim CM, Koike K, Saito I, Miyamura T, Jay G . (1991). HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351: 317–320.

    Article  CAS  PubMed  Google Scholar 

  • Kinoshita K, Nonaka T . (2006). The dark side of activation-induced cytidine deaminase: relationship with leukemia and beyond. Int J Hematol 83: 201–207.

    Article  CAS  PubMed  Google Scholar 

  • Koike K, Moriya K, Iino S, Yotsuyanagi H, Endo Y, Miyamura T et al. (1994). High-level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice. Hepatology 19: 810–819.

    Article  CAS  PubMed  Google Scholar 

  • Koike K, Moriya K, Kimura S . (2002). Role of hepatitis C virus in the development of hepatocellular carcinoma: transgenic approach to viral hepatocarcinogenesis. J Gastroenterol Hepatol 17: 394–400.

    Article  CAS  PubMed  Google Scholar 

  • Komori J, Marusawa H, Machimoto T, Endo Y, Kinoshita K, Kou T et al. (2008). Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. Hepatology 47: 888–896.

    Article  CAS  PubMed  Google Scholar 

  • Kotani A, Okazaki IM, Muramatsu M, Kinoshita K, Begum NA, Nakajima T et al. (2005). A target selection of somatic hypermutations is regulated similarly between T and B cells upon activation-induced cytidine deaminase expression. Proc Natl Acad Sci USA 102: 4506–4511.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kou T, Marusawa H, Kinoshita K, Endo Y, Okazaki IM, Ueda Y et al. (2006). Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis. Int J Cancer 120: 469–476.

    Article  Google Scholar 

  • Kues WA, Petersen B, Mysegades W, Carnwath JW, Niemann H . (2005). Isolation of murine and porcine fetal stem cells from somatic tissue. Biol Reprod 72: 1020–1028.

    Article  CAS  PubMed  Google Scholar 

  • Lomeli H, Ramos-Mejia V, Gertsenstein M, Lobe CG, Nagy A . (2000). Targeted insertion of Cre recombinase into the TNAP gene: excision in primordial germ cells. Genesis 26: 116–117.

    Article  CAS  PubMed  Google Scholar 

  • Ma W, Xia X, Stafford LJ, Yu C, Wang F, LeSage G et al. (2006). Expression of GCIP in transgenic mice decreases susceptibility to chemical hepatocarcinogenesis. Oncogene 25: 4207–4216.

    Article  CAS  PubMed  Google Scholar 

  • Maeda S, Kamata H, Luo JL, Leffert H, Karin M . (2005). IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121: 977–990.

    Article  CAS  PubMed  Google Scholar 

  • Marusawa H . (2008). Aberrant AID expression and human cancer development. Int J Biochem Cell Biol 40: 1399–1402.

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T et al. (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 

  • Morgan HD, Dean W, Coker HA, Reik W, Petersen-Mahrt SK . (2004). Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem 279: 52353–52360.

    Article  CAS  PubMed  Google Scholar 

  • Murakami H, Sanderson ND, Nagy P, Marino PA, Merlino G, Thorgeirsson SS . (1993). Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. Cancer Res 53: 1719–1723.

    CAS  PubMed  Google Scholar 

  • Muto T, Okazaki IM, Yamada S, Tanaka Y, Kinoshita K, Muramatsu M et al. (2006). Negative regulation of activation-induced cytidine deaminase in B cells. Proc Natl Acad Sci USA 103: 2752–2757.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nakau M, Miyoshi H, Seldin MF, Imamura M, Oshima M, Taketo MM . (2002). Hepatocellular carcinoma caused by loss of heterozygosity in Lkb1 gene knockout mice. Cancer Res 62: 4549–4553.

    CAS  PubMed  Google Scholar 

  • Okazaki IM, 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 Central  PubMed  Google Scholar 

  • Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P et al. (2007). Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28: 622–629.

    Article  CAS  PubMed  Google Scholar 

  • Riehle KJ, Campbell JS, McMahan RS, Johnson MM, Beyer RP, Bammler TK et al. (2008). Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3. J Exp Med 205: 91–103.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sakurai T, Maeda S, Chang L, Karin M . (2006). Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation. Proc Natl Acad Sci USA 103: 10544–10551.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sandgren EP, Quaife CJ, Pinkert CA, Palmiter RD, Brinster RL . (1989). Oncogene-induced liver neoplasia in transgenic mice. Oncogene 4: 715–724.

    CAS  PubMed  Google Scholar 

  • Schreck S, Buettner M, Kremmer E, Bogdan M, Herbst H, Niedobitek G . (2006). Activation-induced cytidine deaminase (AID) is expressed in normal spermatogenesis but only infrequently in testicular germ cell tumours. J Pathol 210: 26–31.

    Article  CAS  PubMed  Google Scholar 

  • Sell S . (2001). Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 33: 738–750.

    Article  CAS  PubMed  Google Scholar 

  • Thorgeirsson SS, Grisham JW . (2002). Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 31: 339–346.

    Article  CAS  PubMed  Google Scholar 

  • Tsuji M, Suzuki K, Kitamura H, Maruya M, Kinoshita K, Ivanov II et al. (2008). Requirement for lymphoid tissue-inducer cells in isolated follicle formation and T cell-independent immunoglobulin a generation in the gut. Immunity 29: 261–271.

    Article  CAS  PubMed  Google Scholar 

  • Urven LE, Weng DE, Schumaker AL, Gearhart JD, McCarrey JR . (1993). Differential gene expression in fetal mouse germ cells. Biol Reprod 48: 564–574.

    Article  CAS  PubMed  Google Scholar 

  • Vogelstein B, Kinzler KW . (2004). Cancer genes and the pathways they control. Nat Med 10: 789–799.

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Duan E, Sung LY, Jeong BS, Yang X, Tian XC . (2005). Generation and characterization of pluripotent stem cells from cloned bovine embryos. Biol Reprod 73: 149–155.

    Article  CAS  PubMed  Google Scholar 

  • Yoshikawa K, Okazaki IM, Eto T, Kinoshita K, Muramatsu M, Nagaoka H et al. (2002). AID enzyme-induced hypermutation in an actively transcribed gene in fibroblasts. Science 296: 2033–2036.

    Article  CAS  PubMed  Google Scholar 

  • Zuker M . (2003). Mfold web server for nucleic acid folding and hybridization prediction. Nucleic Acids Res 31: 3406–3415.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Andras Nagy for his generous gift of TNAP-Cre mice, Dr Takashi Shinohara for suggesting the choice of the Cre mouse strain, Dr Yoshinobu Toda for the preparation of tissue sections and Dr Masayuki Tsuji for technical help with the immunohistochemical analyses. We also thank Dr Sidonia Fagarasan for critical reading of the manuscript and discussions. This study was supported by Grant-in-Aid for Scientific Research (17013042 and 18390122) and the Takeda Science Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to K Kinoshita.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takai, A., Toyoshima, T., Uemura, M. et al. A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations. Oncogene 28, 469–478 (2009). https://doi.org/10.1038/onc.2008.415

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.415

Keywords

This article is cited by

Search

Quick links