Skip to main content

Some NLM-NCBI services and products are experiencing heavy traffic, which may affect performance and availability. We apologize for the inconvenience and appreciate your patience. For assistance, please contact our Help Desk at info@ncbi.nlm.nih.gov.

Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1999 Dec;90(12):1301–1309. doi: 10.1111/j.1349-7006.1999.tb00712.x

β‐Catenin Accumulation and Mutation of Exon 3 of the β‐Catenin Gene in Hepatocellular Carcinoma

Yutaka Kondo 1,2, Yae Kanai 1, Michiie Sakamoto 1, Takuya Genda 1, Masashi Mizokami 2, Ryuzo Ueda 2, Setsuo Hirohashi 1,
PMCID: PMC5926034  PMID: 10665646

Abstract

study was conducted to clarify the contribution of β‐catenin accumulation and mutation of the β‐catenin gene to hepatocarcinogenesis. β‐Catenin accumulation was examined immunohistochemically in 38 paired samples of hepatocellular carcinoma (HCC) and corresponding non‐cancerous liver tissue. Gene mutation was analyzed by polymerase chain reaction‐single strand conformation polymorphism (PCR‐SSCP) and direct sequencing using intronic primers encompassing exon 3. Neither accumulation nor mutation was detected in non‐cancerous liver tissues that showed no remarkable histological features, chronic hepatitis or liver cirrhosis. Accumulation of β‐catenin was seen in the nucleus, cytoplasm or cell membrane in 15 of 38 (39%) HCC samples, and gene mutation was seen in 9 of 38 (24%) HCC samples. Although there was a significant correlation between accumulation and mutation (P<0.01), six HCCs without mutation also showed accumulation. Samples of early HCC showed neither accumulation nor mutation, and accumulation and mutation were each correlated significantly with portal vein tumor involvement (P<0.05). The present results indicate that (1) mutation of exon 3 of the β‐catenin gene can lead to β‐catenin accumulation, although other mechanisms of accumulation may also operate in HCC, and (2) β‐catenin accumulation and mutation of the β‐catenin gene are not early events in hepatocarcinogenesis, and may be associated with the malignant progression of HCC.

Keywords: Hepatocellular carcinoma, β‐Catenin, Single strand conformation polymorphism

Full Text

The Full Text of this article is available as a PDF (3.8 MB).

REFERENCES

  • 1. ) Takeichi , M.The cadherins: cell‐cell adhesion molecules controlling animal morphogenesis . Development , 102 , 639 – 655 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Takeichi , M.Cadherin cell adhesion receptors as a morphogenetic regulator . Science , 251 , 1451 – 1455 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 3. ) Hinck , L. , Nelson , W. J. and Papkoff , J.Wnt‐1 modulates cell‐cell adhesion in mammalian cells by stabilizing β‐catenin binding to the cell adhesion protein cadherin . J Cell Biol. , 124 , 729 – 741 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. ) Funayama , N. , Fagotto , F. , McCrea , P. and Gumbiner , B. M.Embryonic axis induction by the armadillo repeat domain of β‐catenin: evidence for intracellular signaling . J Cell Biol. , 128 , 959 – 968 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. ) Munemitsu , S. , Albert , I. , Souza , B. , Rubinfeld , B. and Polakis , P.Regulation of intracellular β‐catenin levels by the adenomatous polyposis coli (APC) tumor‐suppressor protein . Proc. Natl. Acad. Sci. USA , 92 , 3046 – 3050 ( 1995. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. ) Rubinfeld , B. , Albert , I. , Porfiri , E. , Fiol , C. , Munemitsu , S. and Polakis , P.Binding of GSK3β to the APC‐β‐catenin complex and regulation of complex assembly . Science , 272 , 1023 – 1026 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Morin , P. J. , Sparks , A. B. , Korinek , V. , Barker , N. , Clevers , H. , Vogelstein , B. and Kinzler , K. W.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]
  • 8. ) Rubinfeld , B. , Robbins , P. , El‐Gamil , M. , Albert , I. , Porfiri , E. and Polakis , P.Stabilization of β‐catenin by genetic defects in melanoma cell lines . Science , 275 , 1790 – 1792 ( 1997. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) 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]
  • 10. ) Behrens , J. , Von Kries , J. P. , 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]
  • 11. ) 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]
  • 12. ) de La Coste , A. , Romagnolo , B. , Billuart , P. , Renard , C. A. , Buendia , M. A. , 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]
  • 13. ) Kanai , T. , Hirohashi , S. , Upton , M. P. , Noguchi , M. , Kishi , K. , Makuuchi , M. , Yamasaki , S. , Hasegawa , H. , Takayasu , K. , Moriyama , N. and Shimosato , Y.Pathology of small hepatocellular carcinoma. A proposal for a new gross classification . Cancer , 60 , 810 – 819 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 14. ) Sakamoto , M. , Hirohashi , S. and Shimosato , Y.Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma . Hum. Pathol. , 22 , 172 – 178 ( 1991. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Edmondson , H. A. and Steiner , P. E.Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies . Cancer , 7 , 462 – 503 ( 1954. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Fukuchi , T. , Sakamoto , M. , Tsuda , H. , Maruyama , K. , Nozawa , S. and Hirohashi , S.β‐Catenin mutation in carcinoma of the uterine endometrium . Cancer Res. , 58 , 3526 – 3528 ( 1998. ). [PubMed] [Google Scholar]
  • 17. ) Saito , A. , Kanai , Y. , Maesawa , C. , Ochiai , A. , Torii , A. and Hirohashi , S.Disruption of E‐cadherin‐mediated cell adhesion systems in gastric cancers in young patients . Jpn. J. Cancer Res. , 90 , 993 – 999 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. ) Sambrook , J. , Fritsch , E. F. and Maniatis , T. “ Molecular Cloning: A Laboratory Manual ,” 2nd Ed. , pp. E.3 – E.4 ( 1989. ). Cold Spring Harbor Laboratory; , Cold Spring Harbor , NY . [Google Scholar]
  • 19. ) Emmert‐Buck , M. R. , Bonner , R. F. , Smith , P. D. , Chuaqui , R. F. , Zhuang , Z. , Goldstein , S. R. , Weiss , R. A. and Liotta , L. A.Laser capture microdissection . Science , 274 , 998 – 1001 ( 1996. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) He , T. C. , Sparks , A. B. , Rago , C. , Hermeking , H. , Zawel , L. , da Costa , L. T. , Morin , P. J. , Vogelstein , B. and Kinzler , K. W.Identification of c‐MYC as a target of the APC pathway . Science , 281 , 1509 – 1512 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Mann , B. , Gelos , M. , Siedow , A. , Hanski , M. L. , Gratchev , A. , Ilyas , M. , Bodmer , W. F. , Moyer , M. P. , Riecken , E. O. , Buhr , H. J. and Hanski , C.Target genes of β‐catenin‐T cell‐factor/lymphoid‐enhancer‐factor signaling in human colorectal carcinomas . Proc. Natl. Acad. Sci. USA , 96 , 1603 – 1608 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. ) Tetsu , O. and McCormick , F.β‐Catenin regulates expression of cyclin D1 in colon carcinoma cells . Nature , 398 , 422 – 426 ( 1999. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Oyama , T. , Kanai , Y. , Ochiai , A. , Akimoto , S. , Oda , T. , Yanagihara , K. , Nagafuchi , A. , Tsukita , S. , Shibamoto , S. , Ito , F. , Takeichi , M. , Matsuda H. and Hirohashi , S.A truncated β‐catenin disrupts the interaction between E‐cadherin and β‐catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines . Cancer Res. , 54 , 6282 – 6287 ( 1994. ). [PubMed] [Google Scholar]
  • 24. ) Horii , A. , Nakatsuru , S. , Miyoshi , Y. , Ichii , S. , Nagase , H. , Ando , H. , Yanagisawa , A. , Tsuchiya , E. , Kato , Y. and Nakamura , Y.Frequent somatic mutations of the APC gene in human pancreatic cancer . Cancer Res. , 52 , 6696 – 6698 ( 1992. ). [PubMed] [Google Scholar]
  • 25. ) Chen , T. C. , Hsieh , L. L. , Ng , K. F. , Jeng , L. B. and Chen , M. F.Absence of APC gene mutation in the mutation cluster region in hepatocellular carcinoma . Cancer Lett. , 134 , 23 – 28 ( 1998. ). [DOI] [PubMed] [Google Scholar]
  • 26. ) Behrens , J. , Jerchow , B. A. , Wurtele , M. , Grimm , J. , Asbrand , C. , Wirtz , R. , Kuhl , M. , Wedlich , D. and Birchmeier , W.Functional interaction of an axin homolog, conductin, with β‐catenin, APC, and GSK3β . Science , 280 , 596 – 599 ( 1998. ). [DOI] [PubMed] [Google Scholar]

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

RESOURCES