Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1999 Aug;90(8):824–828. doi: 10.1111/j.1349-7006.1999.tb00822.x

β‐Catenin (Ctnnb1) Gene Mutations in Diethylnitrosamine (DEN)‐induced Liver Tumors in Male F344 Rats

Yasuhiro Yamada 1,✉, Naoki Yoshimi 1, Shigeyuki Sugie 1, Masumi Suzui 2, Kengo Matsunaga 1, Kunihiro Kawabata 1, Akira Hara 1, Hideki Mori 1
PMCID: PMC5926152  PMID: 10543253

Abstract

Alterations in multiple phosphorylation sites on exon 3 of the β‐catenin gene have recently been implicated in hepatocarcinogenesis in humans as well as mice. To identify genetic alterations which could be involved in the chemical‐induced hepatocarcinogenesis of rats, we analyzed the status of the sites in the β‐catenin gene (Ctnnb1) of liver neoplasms induced by diethylnitrosamine (DEN) in male F344 rats, using the polymerase chain reaction‐single strand conformation polymorphism method. In the present investigation, we examined 35 hepatocellular neoplasms (28 adenomas and 7 carcinomas) for the expression of mutations in the region of the β‐catenin gene. Point mutation at codon 32, 35, 37 or 41, which has been reported in human and mouse liver cell carcinomas and/or other cancers, was recognized in eleven (31%) out of 35 lesions (8 adenomas and 3 carcinomas). Our results indicate that Ctnnb1 mutations may contribute to hepatocarcinogenesis in rats. Our finding that Ctnnb1 mutation was present in adenomas as well as carcinomas also suggests that the mutation is a relatively early event in DEN‐induced hepatocarcinogenesis in rats.

Keywords: β‐Catenin, Mutation, Hepatocarcinogenesis, Rat, Diethylnitrosamine

Full Text

The Full Text of this article is available as a PDF (328.8 KB).

REFERENCES

  • 1).Molenaar , M. , Wetering , M. V. D. , Oosterwegel , M. , Peterson‐Maduro , J. , Godsave , S. , Korinek , V. , Roose , J. , Destree , O. and Clevers , H.XTcf‐3 transcription factor mediates β‐catenin‐induced axis formation in Xenopus embryos . Cell , 86 , 391 – 399 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 2).Behrens , J. , Kries , J. V. , Kuhl , M. , Bruhn , L. , Wedlich , D. , Grosschedl , R. and Birchmeier , W.Functional interaction of β‐catenin with the transcription factor LEF‐1 . Nature , 382 , 638 – 642 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 3).Korinek , V. , Barker , N. , Morin , P. , Wichen , D. V. , Weger , R. D. , Kinzler , K. , Vogelstein , B. and Clevers , H.Constitutive transcriptional activation by a β‐catenin‐Tcf complex in APC‐1‐colon carcinoma . Science , 275 , 1784 – 1787 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 4).Wetering , M. V. D. , Cavallo , R. , Dooijes , D. , Beest , M. V. , Es , J. V. , Loureiro , J. , Ypma , A. , Hursh , D. , Jones , T. , Bejsovec , A. , Peifer , M. , Mortin , M. and Clevers , H.Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF . Cell , 88 , 789 – 799 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 5).Jeon , S. , Jeong , S. , Lee , C. , Kim , J. , Kim , Y. , Chung , H. , Park , S. and Seong , R.Expression of Tcf‐1 mRNA and surface TCR‐CD3 complexes are reduced during apoptosis of T cells . Int. Immunol. , 10 , 1519 – 1527 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 6).Young , C. , Kitamura , M. , Hardy , S. and Kitajewski , J.Wnt‐1 induces growth, cytosolic β‐catenin, and Tcf/Lef transcriptional activation in Rat‐1 fibroblasts . Mol. Cell. Biol. , 18 , 2474 – 2485 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7).Aberle , H. , Bauer , A. , Stappert , J. , Kispert , A. and Kemler , R.β‐Catenin is a target for the ubiquitin‐proteasome pathway . EMBO J. , 16 , 3797 – 3804 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8).Orford , K. , Crockett , C. , Jensen , J. , Weissman , A. and Byers , S.Serine phosphorylation‐regulated ubiquitination and degradation of β‐catenin . J. Biol. Chem. , 272 , 24735 – 24738 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 9).Morin , P. , Sparks , A. , Korinek , V. , Barker , N. , Clevers , Vogelstein B. and Kinzler , K.Activation of β‐catenin‐Tcf signaling in colon cancer by mutations in β‐catenin or APC . Science , 275 , 1787 – 1790 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 10).Zurawel , R. , Chiappa , S. , Allen , C. and Raffel , C.Sporadic medulloblastomas contain oncogenic β‐catenin mutations . Cancer Res. , 58 , 896 – 899 ( 1998. ). [PubMed] [Google Scholar]
  • 11).Palacios , J. and Gamallo , C.Mutations in the β‐catenin gene (CTNNB1) in endometrioid ovarian carcinomas . Cancer Res. , 58 , 1344 – 1347 ( 1998. ). [PubMed] [Google Scholar]
  • 12).Voeller , H. , Truica , C. and Gelmann , E.β‐Catenin mutations in human prostate cancer . Cancer Res. , 58 , 2520 – 2523 ( 1998. ). [PubMed] [Google Scholar]
  • 13).Dragan , Y. , Hully , J. , Nakamura , J. , Mass , M. , Swenberg , J. and Pitot , H.Biochemical events during initiation of rat hepatocarcinogenesis . Carcinogenesis , 15 , 1451 – 1458 ( 1994. ). [DOI] [PubMed] [Google Scholar]
  • 14).Tanaka , T. , Kojima , T. , Kawamori , T. , Yoshimi , N. and Mori , H.Chemoprevention of diethylnitrosamine‐induced hepatocarcinogenesis by a simple phenolic acid protocatechuic acid in rats . Cancer Res. , 53 , 2775 – 2779 ( 1993. ). [PubMed] [Google Scholar]
  • 15).Nakae , D. , Kobayashi , Y. , Akai , H. , Andoh , N. , Satoh , H. , Ohashi , K. , Tsutsumi , M. and Konishi , Y.Involvement of 8‐hydroxyguanine formation in the initiation of rat liver car cinogenesis by low dose levels of N‐nitrosodiethylamine . Cancer Res. , 57 , 1281 – 1287 ( 1997. ). [PubMed] [Google Scholar]
  • 16).Omori , Y. , Krutovskikh , V. , Mironov , N. , Tsuda , H. and Yamasaki , H.Cx32 gene mutation in a chemically induced rat liver tumour . Carcinogenesis , 17 , 2077 – 2080 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 17).Mills , J. , Falls , J. , Souza , A. D. and Jirtle , R.Imprinted M6p/Igf2 receptor is mutated in rat liver tumors . Oncogene , 16 , 2797 – 2802 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 18).Miyoshi , Y. , Iwao , K. , Nagasawa , Y. , Aihara , T. , Sasaki , Y. , Imaoka , S. , Murata , M. , Shimano , T. and Nakamura , Y.Activation of the β‐catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3 . Cancer Res. , 58 , 2524 – 2527 ( 1998. ). [PubMed] [Google Scholar]
  • 19).Coste , A. D. L. , Romagnolo , B. , Billuart , P. , Renard , C. , Buendia , M. , Soubrane , O. , Fabre , M. , Chelly , J. , Beldjord , C. , Kahn , A. and Perret , C.Somatic mutations of the β‐catenin gene are frequent in mouse and human hepatocellular carcinomas . Proc. Natl. Acad. Sci. USA , 95 , 8847 – 8851 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20).Takahashi , M. , Fukuda , K. , Sugimura , T. and Wakabayashi , K.β‐Catenin is frequently mutated and demonstrates altered cellular location in azoxymethane‐induced rat colon tumors . Cancer Res. , 58 , 42 – 46 ( 1998. ). [PubMed] [Google Scholar]
  • 21).Suzui , M. , Yoshimi , N. , Dashwood , R. , Ushijima , T. , Sugimura , T. , Mori , H. and Nagao , M.Frequent mutations in the rat β‐catenin gene (Ctnnb1) of ulcerative colitis‐associated colon cancer induced by 1‐hydroxyanthraquinone and methylazoxymethanol acetate . Mol. Carcinog. , 24 , 232 – 237 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 22).Dashwood , R. , Suzui , M. , Nakagama , H. , Sugimura , T. and Nagao , M.High frequency of β‐catenin (ctnnb1) mutations in the colon tumors induced by two heterocyclic amines in the F344 rat . Cancer Res. , 58 , 1127 – 1129 ( 1998. ). [PubMed] [Google Scholar]
  • 23).Squire , R. and Levitt , M.Report of a workshop on classification of specific hepatocellular lesions in rats . Cancer Res. , 35 , 3214 – 3223 ( 1975. ). [PubMed] [Google Scholar]
  • 24).Maronpot , R. , Montgomery , C. , Boorman , G. and McConnell , E.National toxicology program nomenclature for hepatoproliferative lesions of rats . Toxicol. Pathol. , 14 , 263 – 273 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 25).Iwao , K. , Nakamori , S. , Kameyama , M. , Imaoka , S. , Kinoshita , M. , Fukui , T. , Ishiguro , S. , Nakamura , Y. and Miyoshi , Y.Activation of the β‐catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations . Cancer Res. , 58 , 1021 – 1026 ( 1998. ). [PubMed] [Google Scholar]
  • 26).Ilyas , M. , Tomlinson , I. , Rowan , A. , Pignatelli , M. and Bodmer , W.β‐Catenin mutations in cell lines established from human colorectal cancers . Proc. Natl. Acad. Sci. USA , 94 , 10330 – 10334 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27).Sparks , A. , Morin , P. , Vogelstein , B. and Kinzler , K.Mutational analysis of the APC/β‐catenin/Tcf pathway in colorectal cancer . Cancer Res. , 58 , 1130 – 1134 ( 1998. ). [PubMed] [Google Scholar]
  • 28).Yost , C. , Torres , M. , Miller , J. , Huang , E. , Kimelman , D. and Moon , R.The axis‐inducing activity, stability, and sub‐cellular distribution of β‐catenin is regulated in Xenopus embryos by glycogen synthase kinase 3 . Genes Dev. , 10 , 1443 – 1454 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 29).Munemitsu , S. , Albert , I. , Rubinfeld , B. and Polakis , P.Deletion of an amino‐terminal sequence β‐catenin in vivo and promotes hyperphosphorylation of the adenomatous polyposis coli tumor suppressor protein . Mol. Cell. Biol. 16 , 4088 – 4094 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30).Aberle , H. , Bauer , A. , Stappert , J. , Kispert , A. and Kemler , R.β‐Catenin is a target for the ubiquitin‐proteasome pathway . EMBO J. , 16 , 3797 – 3804 ( 1997. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31).He , T. , Sparks , A. , Rago , C. , Hermeking , H. , Zawel , L. , Costa , L. D. , Morin , P. , Vogelstein , B. and Kinzler , K.Identification of c‐MYC as a target of the APC pathway . Science , 281 , 1509 – 1512 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 32).Beer , D. , Schwarz , M. , Sawada , N. and Pitot , H.Expression of H‐ras and c‐myc protooncogenes in isolated gamma‐glutamyl transpeptidase‐positive rat hepatocytes and in hepatocellular carcinomas induced by diethylnitrosamine . Cancer Res. , 46 , 2435 – 2441 ( 1986. ). [PubMed] [Google Scholar]
  • 33).Himeno , Y. , Fukuda , Y. , Hatanaka , M. and Imura , H.Expression of oncogenes during rat chemical hepatotumorigenesis promoted by estrogen . Jpn. J. Cancer Res. , 80 , 737 – 742 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34).Pascale , R. , Miglio , M. D. , Muroni , M. , Simile , M. , Daino , L. , Seddaiu , M. , Nufris , A. , Gaspa , L. , Deiana , L. and Feo , F.c‐Myc amplification in pre‐malignant and malignant lesions induced in rat liver by the resistant hepatocyte model . Int. J. Cancer , 68 , 136 – 142 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 35).Hirota , N. and Williams , G.The sensitivity and heterogeneity of histochemical markers for altered foci involved in liver carcinogenesis . Am. J. Pathol. , 95 , 317 – 328 . [PMC free article] [PubMed] [Google Scholar]
  • 36).Vogelstein , B. and Kinzler , K. “ The Genetic Basis of Human Cancer ” pp . 565 – 587 ( 1998. ). McGraw‐Hill; , New York . [Google Scholar]
  • 37).Su , L. , Kinzler , K. , Vogelstein , B. , Preisinger , A. , Moser , A. , Luongo , C. , Gould , K. and Dove , W.Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene . Science , 256 , 668 – 670 ( 1992. ). [DOI] [PubMed] [Google Scholar]
  • 38).Oshima , M. , Oshima , H. , Kitagawa , K. , Kobayashi , M. , Itakura , C. and Taketo , M.Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene . Proc. Natl. Acad. Sci. USA , 92 , 4482 – 4486 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES