Analysis of the β‐Catenin/T Cell Factor Signaling Pathway in 36 Gastrointestinal and Liver Cancer Cells (original) (raw)

Abstract

We investigated the frequency and mechanism of |bT‐catenin/T cell factor (Tcf) signaling activation in a panel of 36 human gastrointestinal and liver cancer cell lines. Reporter assay and electrophoretic mobility shift assay revealed that the β‐catenin/Tcf signaling was upregulated in 12 of 12 (100%) colorectal, 5 of 8 (68%) gastric, 2 of 7 (29%) hepatic, and none of 9 pancreatic cancer cell lines. The activation of the pathway was mainly due to the mutation of adenomatous polyposis coli (APC) or β‐catenin, and Tcf‐4 was highly expressed in these cell lines with upregulated signaling. Nuclear β‐catenin was observed not only in the signaling‐activated cell lines, but also in 14 of 25 (56%) primary gastric cancers, 15 of 20 (75%) colon cancers, 5 of 19 (26%) hepatocellular carcinomas, and none of 13 pancreatic cancers. The presence of signaling‐upregulated gastric cancer cell lines with intact APC and β‐catenin suggests the involvement of other mechanisms than mutations of APC or β‐catenin.

Keywords: β‐Catenin, APC, GSK‐3β, T cell factor, Gastrointestinal cancer

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

REFERENCES

• 1.) Fearnhead , N. S. , Britton , M. P. and Bodmer , W. F.The ABC of APC . Hum. Mol. Genet. , 10 , 721 – 733 ( 2001. ). [DOI] [PubMed] [Google Scholar]
• 2.) Barker , N. , Morin , P. J. and Clevers , H.The Yin‐Yang of TCF/beta‐catenin signaling . Adv. Cancer Res. , 77 , 1 – 24 ( 2000. ). [DOI] [PubMed] [Google Scholar]
• 3.) 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]
• 4.) Korinek , V. , Barker , N. , Morin , P. J. , van Wichen , D. , de Weger , R. , Kinzler , K. W. , Vogelstein , B. and Clevers , H.Constitutive transcriptional activation by a β‐catenin‐Tcf complex in APC‐/‐ colon carcinoma . Science , 275 , 1784 – 1787 ( 1997. ). [DOI] [PubMed] [Google Scholar]
• 5.) 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]
• 6.) Tetsu , O. and McCormick , F.Beta‐catenin regulates expression of cyclin D1 in colon carcinoma cells . Nature , 398 , 422 – 426 ( 1999. ). [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.) Polakis , P.Wnt signaling and cancer . Genes Dev. , 14 , 1837 – 1851 ( 2000. ). [PubMed] [Google Scholar]
• 9.) Ijichi , H. , Ikenoue , T. , Kato , N. , Mitsuno , Y. , Togo , G. , Kato , J. , Kanai , F. , Shiratori , Y. and Omata , M.Systematic analysis of the TGF‐beta‐Smad signaling pathway in gastrointestinal cancer cells . Biochem. Biophys. Res. Commun. , 289 , 350 – 357 ( 2001. ). [DOI] [PubMed] [Google Scholar]
• 10.) Ikeda , Y. , Ezaki , M. , Hayashi , L , Yasuda , D. , Nakayama , K. and Kono , A.Establishment and characterization of human pancreatic cancer cell lines in tissue culture and in nude mice . Jpn. J. Cancer Res. , 81 , 987 – 993 ( 1990. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
• 11.) Ochiai , A. , Yasui , W. and Tahara , E.Growth‐promoting effect of gastrin on human gastric carcinoma cell line TMK1 . Jpn. J. Cancer Res. , 76 , 1064 – 1071 ( 1985. ). [PubMed] [Google Scholar]
• 12.) Yasoshima , T. , Denno , R. , Kawaguchi , S. , Sato , N. , Okada , Y. , Ura , H. , Kikuchi , K. and Hirata , K.Establishment and characterization of human gastric carcinoma lines with high metastatic potential in the liver: changes in integrin expression associated with the ability to metastasize in the liver of nude mice . Jpn. J. Cancer Res. , 87 , 153 – 160 ( 1996. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
• 13.) Terris , B. , Pineau , P. , Bregeaud , L. , Valla , D. , Belghiti , J. , Tiollais , P. , Degott , C. and Dejean , A.Close correlation between β‐catenin gene alterations and nuclear accumulation of the protein in human hepatocellular carcinomas . Oncogene , 18 , 6583 – 6588 ( 1999. ). [DOI] [PubMed] [Google Scholar]
• 14.) Barker , N. , Huls , G. , Korinek , V. and Clevers , H.Restricted high level expression of Tcf‐4 protein in intestinal and mammary gland epithelium . Am. J. Pathol. , 154 , 29 – 35 ( 1999. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
• 15.) Schreiber , E. , Matthias , P. , Muller , M. M. and Schaffner , W.Rapid detection of octamer binding proteins with ‘miniextracts’ prepared from a small number of cells . Nucleic Acids Res. , 17 , 6419 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
• 16.) Prosser , J. , Condie , A. , Wright , M. , Horn , J. M. , Fantes , J. A. , Wyllie , A. H. and Dunlop , M. G.APC mutation analysis by chemical cleavage of mismatch and a protein truncation assay in familial adenomatous polyposis . Br. J. Cancer , 70 , 841 – 846 ( 1994. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
• 17.) van der Luijt , R. , Khan , P. M. , Vasen , H. , van Leeuven , C. , Tops , C. , Roest , P. , den Dunnen , J. and Fodde , R.Rapid detection of translation terminating mutations at the adenomatous polyposis coli (APC) gene by direct protein truncation test . Genomics , 20 , 1 – 4 ( 1994. ). [DOI] [PubMed] [Google Scholar]
• 18.) Ikenoue , T. , Togo , G. , Nagai , K. , Ijichi , H. , Kato , J. , Yamaji , Y. , Okamoto , M. , Kato , N. , Kawabe , T. , Tanaka , A. , Matsumura , M. , Shiratori , Y. and Omata , M.Frameshift mutations at mononucleotide repeats in RAD50 recombinational DNA repair gene in colorectal cancer with microsatellite instability . Jpn. J. Cancer Res. , 92 , 587 – 591 ( 2001. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
• 19.) Rowan , A. J. , Lamlum , H. , Ilyas , M. , Wheeler , J. , Straub , J. , Papadopoulou , A. , Bicknell , D. , Bodmer , W. F. and Tomlinson , I. P.APC mutations in sporadic colorectal tumors: a mutational “hotspot” and interdependence of the “two hits.” Proc. Natl. Acad. Sci. USA , 97 , 3352 – 3357 ( 2000. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
• 20.) 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]
• 21.) Furuhashi , M. , Yagi , K. , Yamamoto , H. , Furukawa , Y. , Shimada , S. , Nakamura , Y. , Kikuchi , A. , Miyazono , K. and Kato , M.Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway . Mol. Cell. Biol. , 21 , 5132 – 5141 ( 2001. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
• 22.) Castrop , J. , van Norren , K. and Clevers , H.A gene family of HMG‐box transcription factors with homology to TCF‐1 . Nucleic Acids Res. , 20 , 611 ( 1992. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
• 23.) Porfiri , E. , Rubinfeld , B. , Albert , I. , Hovanes , K. , Waterman , M. and Polakis , P.Induction of a β‐catenin LEF‐1 complex by wnt‐1 and transforming mutants of β‐catenin . Oncogene , 15 , 2833 – 2839 ( 1997. ). [DOI] [PubMed] [Google Scholar]
• 24.) Sparks , A. B. , Morin , P. J. , Vogelstein , B. and Kinzler , K. W.Mutational analysis of the APC/β‐catenin/Tcf pathway in colorectal cancer . Cancer Res. , 58 , 1130 – 1134 ( 1998. ). [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.) Horii , A. , Nakatsuru , S. , Miyoshi , Y. , Ichii , S. , Nagase , H. , Kato , Y. , Yanagisawa , A. and Nakamura , Y.The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer . Cancer Res. , 52 , 3231 – 3233 ( 1992. ). [PubMed] [Google Scholar]
• 27.) Powell , S. M. , Cummings , O. W. , Mullen , J. A. , Asghar , A. , Fuga , G. , Piva , P. , Minacci , C. , Megha , T. , Tosi , P. and Jackson , C. E.Characterization of the APC gene in sporadic gastric adenocarcinomas . Oncogene , 12 , 1953 – 1959 ( 1996. ). [PubMed] [Google Scholar]
• 28.) Park , W. S. , Oh , R. R. , Park , J. Y. , Lee , S. H. , Shin , M. S. , Kim , Y. S. , Kim , S. Y. , Lee , H. K. , Kim , P. J. , Oh , S. T. , Yoo , N. J. and Lee , J. Y.Frequent somatic mutations of the beta‐catenin gene in intestinal‐type gastric cancer . Cancer Res. , 59 , 4257 – 4260 ( 1999. ). [PubMed] [Google Scholar]
• 29.) Satoh , S. , Daigo , Y. , Furukawa , Y. , Kato , T. , Miwa , N. , Nishiwaki , T. , Kawasoe , T. , Ishiguro , H. , Fujita , M. , Tokino , T. , Sasaki , Y. , Imaoka , S. , Murata , M. , Shimano , T. , Yamaoka , Y. and Nakamura , Y.AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus‐mediated transfer of AXIN1 . Nat. Genet. , 24 , 245 – 250 ( 2000. ). [DOI] [PubMed] [Google Scholar]
• 30.) Liu , W. , Dong , X. , Mai , M. , Seelan , R. S. , Taniguchi , K. , Krishnadath , K. K. , Hailing , K. C. , Cunningham , J. M. , Boardman , L. A. , Qian , C. , Christensen , E. , Schmidt , S. S. , Roche , P. C. , Smith , D. I. and Thibodeau , S. N.Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating beta‐catenin/TCF signalling . Nat. Genet , 26 , 146 – 147 ( 2000. ). [DOI] [PubMed] [Google Scholar]
• 31.) Clarke , A. R. , Cummings , M. C. and Harrison , D. J.Interaction between murine germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to increased intestinal malignancy . Oncogene , 11 , 1913 – 1920 ( 1995. ). [PubMed] [Google Scholar]
• 32.) 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]
• 33.) McKie , A. B. , Filepe , M. I. and Lemoine , N. R.Abnormalities affecting the APC and MCC tumor suppressor gene loci on chromosome 5q occur frequently in gastric cancer but not in pancreatic cancer . Int. J. Cancer , 55 , 598 – 603 ( 1993. ). [DOI] [PubMed] [Google Scholar]
• 34.) Gerdes , B. , Ramaswamy , A. , Simon , B. , Pietsch , T. , Bastian , D. , Kersting , M. , Moll , R. and Bartsch , D.Analysis of beta‐catenin gene mutations in pancreatic tumors . Digestion , 60 , 544 – 548 ( 1999. ). [DOI] [PubMed] [Google Scholar]