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Mutations of the APC, beta-catenin, and axin 1 genes and cytoplasmic accumulation of beta-catenin in oral squamous cell carcinoma

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Abstract

Purpose: The Wnt pathway is involved in carcinogenesis and three regulatory genes of the Wnt pathway, APC, beta-catenin and Axin are mutated in some primary human cancers. Mutations in these genes can impair the down regulation of beta-catenin, which results in the stabilization of beta-catenin, accumulation of free beta-catenin and subsequent activation of the Wnt pathway. To clarify the genetic alterations of components of the Wnt pathway in oral squamous cell carcinoma (SCC), we examined mutations in the APC, beta-catenin and Axin genes and subcellular localization of beta-catenin. Methods: 20 oral SCC tissues and four cell lines derived from oral SCC were used. Mutational analysis was performed by a single-strand conformation polymorphism (SSCP) method and direct sequecing analysis. The samples were also examined by immunohistochemical staining and immunoblot analysis. Results: In 3 of 4 cell lines, mutations were observed in the APC and Axin1 genes without amino acid substitutions. In a clinical sample, a mutation in the Axin1 gene was detected; a T insertion at codon 250 resulted in the formation of a stop codon at codon 259. In addition, cytoplasmic accumulation of beta-catenin was observed in 3 (75%) of 4 cell lines and 18 (90%) of 20 cancer tissue samples. Conclusion: The Axin1 gene may be one of the mutational target in oral SCC. In addition, the cytoplasmic accumulation of beta-catenin is a common characteristic of oral SCC, but is not closely associated with mutational alterations in the APC, beta-catenin and Axin1 genes.

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References

  • Aberle H, Bauer A, Stappert J, Kispert A, Kemler R (1997) Beta-catenin is a target for the ubiquitin-proteasome pathway. EMBO J 16(13):3797–3804

    Article  PubMed  CAS  Google Scholar 

  • Bagutti C, Speight PM, Watt FM (1998) Comparison of integrin, cadherin, and catenin expression in squamous cell carcinomas of the oral cavity. J Pathol 186(1):8–16

    Article  PubMed  CAS  Google Scholar 

  • Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschdl R, Birchmeier W (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382:638–642

    Article  PubMed  CAS  Google Scholar 

  • Boynton RF, Blount PL, Yin J, Brown VL, Huang Y, Tong Y, McDaniel T, Newkirk C, Resau JH, Raskind WH, Haggitt RC, Reid BJ, Meltzer SJ (1992) Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. Proc Natl Acad Sci USA. 15 89(8):3385–3388

    Article  CAS  Google Scholar 

  • Chang KW, Lin SC, Mangold KA, Jean MS, Yuan TC, Lin SN, Chang CS (2000) Alterations of adenomatous polyposis coli (APC) gene in oral squamous cell carcinoma. In J Oral Maxillofac Surg 29:223–226

    Article  CAS  Google Scholar 

  • Chida K, Kato N, Kuroki T (1986) Down regulation of phorbol diester receptors by proteolytic degradation of protein kinase C in a cultured cell line of fetal rat skin keratinocytes. J Biol Chem 261(28):13013–13018

    PubMed  CAS  Google Scholar 

  • D’Amico D, Carbone DP, Johnson BE, Meltzer SJ, Minutesna JD (1992) Polymorphic sites within the MCC and APC loci reveal very frequent loss of heterozygosity in human small cell lung cancer. Cancer Res 1 52(7):1996–1999

    CAS  Google Scholar 

  • Eagle H (1955) Propagation in a fluid medium of a human epidermoid carcinoma, starain KB. Proc Soc Exp Biol Med 89:485–495

    PubMed  Google Scholar 

  • Emmert-Buck MR, Bonner RF, Smith PD, Chuaqui RF, Zhuang Z, Goldstein SR, Weiss RA and Liotta LA (1996) Laser capture microdissection. Science 274:998–1001

    Article  PubMed  CAS  Google Scholar 

  • Fukuchi T, Sakamoto M, Tsuda H, Maruyama K, Nozawa S, Hirohashi S (1998) Beta-catenin mutation in carcinoma of the uterine endometrium. Cancer Res 58:3526–3528

    PubMed  CAS  Google Scholar 

  • Gottardi CJ, Wong E, Gumbiner BM (2001) E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner. J Cell Biol 28 153(5):1049–1060

    Article  Google Scholar 

  • Groden J, Thliveris A, Samowiz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, Sargeant L, Krapcho K, Wolff E, Randall B, Hughes JP, Warrington J, Mcpherson J, Wasmuth J, Le Paslier D, Abderrahim H, Cohen D, Leppert M and White R (1991) Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66:589–600

    Article  PubMed  CAS  Google Scholar 

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B and Kinzler KW (1998) Identification of c-myc as a target of the APC pathway. Science 281:1509–1512

    Article  PubMed  CAS  Google Scholar 

  • Horii A, Nakatsuru S, Miyoshi Y, Ichii S, Nagase H, Ando H, Yanagisawa A, Tsuchiya E, Kato Y, Nakamura Y (1992a) Frequent somatic mutations of the APC gene in human pancreatic cancer. Cancer Res 1 52(23):6696–6698

    CAS  Google Scholar 

  • Horii A, Nakatsuru S, Miyoshi Y, Ichii S, Nagase H, Kato Y, Yanagisawa A, Nakamura Y (1992b) The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer. Cancer Res 1 52(11):3231–3233

    CAS  Google Scholar 

  • Horikoshi M, Kimura Y, Nagura H, Ono T, Ito H (1974) A new human cell line derived from human carcinoma of the gingiva. I. Its establishment and morphological studies. Jpn J Oral Maxillofac Surg 20(2):100–106

    CAS  Google Scholar 

  • Huang JS, Chiang CP, Kok SH, Kuo YS, Kuo MYP. (1997) Loss of heterozygosity APC and MCC genes in oral squamous cell carcinoma in Taiwan. J Oral Pathol Med 26:322–326

    Article  PubMed  CAS  Google Scholar 

  • Iwao K, Nakamori S, Kameyama M, Imaoka S, Kinoshita M, Fukui T, Ishiguro S, Nakamura Y and Miyoshi Y (1998) Activation of the beta-catenin gene by interstitional deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Res 58:1021–1026

    PubMed  CAS  Google Scholar 

  • Jue SF, Bradley RS, Rudnicki JA, Varmus HE, Brown AM (1992) The mouse Wnt-1 gene can act via a paracrine mechanisms in transformation of mammary epithelial cells. Mol Cell Biol 12:321–328

    PubMed  CAS  Google Scholar 

  • Kemler R (1993) From cadherins to catenins: cytoplasmic protein interaction and regulation of cell adhesion. Trends Genet 9:317–321

    Article  PubMed  CAS  Google Scholar 

  • Kikuchi A (2000) Regulation of beta-catenin signaling in the Wnt pathway. Biochem Biophys Res Commun 268:243–248

    Article  PubMed  CAS  Google Scholar 

  • Kondo Y, Kanai Y, Sakamoto M, Genda T, Mizokami M, Ueda R, et al (1999) Beta-catenin accumulation and mutation of exon 3 of the beta-catenin gene in hepatocellular carcinoma. Jpn J Cancer Res 90:1301–1309

    PubMed  CAS  Google Scholar 

  • Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B and Clevers H (1997) Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC −/− colon carcinoma. Science 275:1784–1787

    Article  PubMed  CAS  Google Scholar 

  • de La Coste A, Romangnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A and Perret C (1998) Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 95:8847–8851

    Article  PubMed  Google Scholar 

  • Largey JS, Meltzer SJ, Sauk JJ, Hebert CA, Archibald DW (1994) Loss of heterozygosity involving the APC gene in oral squamous cell carcinomas. Oral Surg Oral Med Oral Pathol 77(3):260–263

    Article  PubMed  CAS  Google Scholar 

  • Lo Muzio L, Staibano S, Pannone G, Grieco M, Mignogna MD, Cerrato A, Testa NF and De Rosa C (1999) Beta- and gamma- catenin expression in oral squamous cell carcinomas. Anticancer Res 19:3817–3826

    PubMed  CAS  Google Scholar 

  • Lo Muzio L, Pannone G, Staibano S, Mignogna M, Grieco M, ramires P, Romito AM, De Rosa G, Piattelli A (2002) WNT-1 expression in basal cell carcinoma of head and neck. An immunohistochemical and confocal study with regard to the intracellular distribution of beta-catenin. Anticancer Res 22:565–576

    PubMed  CAS  Google Scholar 

  • Mann B, Gelos M, Siedow A, Hanski ML, Gratchev A, Ilyas M, Bodmer WF, Moyer MP, Riecken EO, Buhr HJ, Hanski C (1999) Target genes of beta-catenin-T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas. Proc Natl Acad Sci USA 96:1603–1608

    Article  PubMed  CAS  Google Scholar 

  • Miyoshi Y, Nagase H, Ando H, Horii A, Ichii S, Nakatsuru S, Aoki T, Miki Y, Mori T and Nakamura Y (1992) Somatic mutations of the APC gene in colorectal tumors: mutation cluster resion in the APC gene. Hum Mol Genet 1(4):229–233

    Article  PubMed  CAS  Google Scholar 

  • Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, Murata M, Shimamoto T and Nakamura Y (1998) Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon3. Cancer Res 58:2524–2527

    PubMed  CAS  Google Scholar 

  • Momose F, Hirata S, Araida T, Tanaka N, Shioda S (1986) Charactors of three oral squamous cell carcinoma cell lines. J Jpn Stomatol Soc 35:485–495

    Google Scholar 

  • Moreno-Bueno G, Hardisson D, Sanchez C, Sarrio D, Cassia R, Garcia-Rostan G, Prat J, Guo M, Herman JG, Matias-Guiu X, Esteller M, Palacios J (2002) Abnormalities of the APC/beta-catenin pathway in endometrial cancer. Oncogene 21:7981–7990

    Article  PubMed  CAS  Google Scholar 

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B and Kinzler KW (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790

    Article  PubMed  CAS  Google Scholar 

  • Ninomiya I, Endo Y, Fushida S, Sasagawa T, Miyashita T, Fujimura T, Nishimura G, Tani T, Hashimoto T, Yagi M, Shimizu K, Ohta T, Yonemura Y, Inoue M, Sasaki T, Miwa K (2000) Alteration of beta-catenin expression in esophageal squamous-cell carcinoma. Int J Cancer 15 85(6):757–761

    Article  CAS  Google Scholar 

  • Nollet F, Berx G, Molemans F, Van Roy F (1996)Genomic Organization of the Human beta-catenin Gene (CTNNB1). Genomics 32:413–424

    Article  PubMed  CAS  Google Scholar 

  • Nylander K, Schildt EB, Eriksson M, Magnusson A, Mehle C, Roos G (1996) A non-random deletion in the p53 gene in oral squamous cell carcinoma. Br J Cancer 73:1381–1386

    PubMed  CAS  Google Scholar 

  • Omer CA, Miller PJ, Diehl RE, Kral AM (1999) Identification of Tcf4 residues involved in high-affinity beta-catenin binding. Biochem Biophys Res Commun 256:584–590

    Article  PubMed  CAS  Google Scholar 

  • Pirinen RT, Hirvikoski P, Johansson RT, Hollmen S, Kosma V-M (2001) Reduced expression of a-catenin, b-catenin, and g-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer. J Clin Pathol 54:391–395

    Article  PubMed  CAS  Google Scholar 

  • Rhee C-S, Sen M, Lu D, Wu C, Leoni L, Rubin J, Corr M, Carson DA (2002) Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas. Oncogene 21(43):6598–6605

    Article  PubMed  CAS  Google Scholar 

  • Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiri E, Polakis P (1997) Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 275:1790–1792

    Article  PubMed  CAS  Google Scholar 

  • Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishigro H, Fujuta M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y and Nakamura Y (2000) AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 24:245–250

    Article  PubMed  CAS  Google Scholar 

  • Simone NL, Bonner RF, Gillespie JW, Emmert-Buck MR, Liotta LA (1998) Laser-capture microdissection: opening the microscopic frontier to molecular analysis. Trends Genet 14(7):272–276

    Article  PubMed  CAS  Google Scholar 

  • Takahashi K, Kanazawa H, Akiyama Y, Tazaki S, Takahara M, Muto T, Tanzawa H and Sato K (1989) Establishment and characterization of a cell line (SAS) from poorly differentiated human squamous cell carcinoma of the tongue. J Jpn Stomatol Soc 38(1):20–28

    Google Scholar 

  • Taniguchi K, Roberts L, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DN, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W (2002) Mutational spectrum of b-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogenes 21:4863–4871

    Article  CAS  Google Scholar 

  • Tetsu O, McCormick F (1999) beta-catenin regulates expression of cyclinD1 in colon carcinoma cells Nature 398:422–426

    Article  PubMed  CAS  Google Scholar 

  • Uzawa K, Yoshikawa H, Suzuki H, Tanzawa H, Shimazaki J, Seino S and Sato K (1994) Abnormalities of the adonomatous polyposis coli gene in human oral squamous-cell carcinoma. Int J Cancer 58:814–817

    Article  PubMed  CAS  Google Scholar 

  • Williams HK, Sanders DSA, Jankowski JAZ, Landini G, Brown AMS (1998) Expression of cadherins and catenins in oral epithelial dysplasia and squamous cell carcinoma. J Oral Pathol Med 27:308–317

    Article  PubMed  CAS  Google Scholar 

  • Wong CM, Fan ST, Ng IOL (2001) B-catenin mutation and overexpression in hepatocellular carcinoma. Cancer 92:136–145

    Article  PubMed  CAS  Google Scholar 

  • Yeh KT, Chang JG, Lin TH, Wang YF, Chang JY, Shih MC, Lin CC (2003) Correlation between protein expression and epigenetic and mutation changes of Wnt pathway-related genes in oral cancer. Int J Oncol 23(4):1001–1007

    PubMed  CAS  Google Scholar 

  • Yokota N, Nishizawa S, Ohta S, Data H, SugimuraH, Namba H, Maekawa M (2002) Role of Wnt pathway in medulloblastoma oncogenesis. Int J Cancer 101:198–201

    Article  PubMed  CAS  Google Scholar 

  • Zecca M, Basler K, Struhl G (1996) Direct and long-range action of a wingless morphogen gradient. Cell 29 87(5):833–844

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery II, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka, 565-0871, Japan

    Soichi Iwai, Wataru Katagiri, Chie Kong, Shigeki Amekawa, Mitsuhiro Nakazawa & Yoshiaki Yura

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  1. Soichi Iwai
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  2. Wataru Katagiri
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  3. Chie Kong
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  4. Shigeki Amekawa
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  5. Mitsuhiro Nakazawa
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  6. Yoshiaki Yura
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Correspondence to Soichi Iwai.

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Iwai, S., Katagiri, W., Kong, C. et al. Mutations of the APC, beta-catenin, and axin 1 genes and cytoplasmic accumulation of beta-catenin in oral squamous cell carcinoma. J Cancer Res Clin Oncol 131, 773–782 (2005). https://doi.org/10.1007/s00432-005-0027-y

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