β-catenin is a cytoskeleton-associated signaling molecule shown to be elevated in various carcinomas but mostly in colon cancer owing to its impaired degradation. In contrast, its close homologue plakoglobin was shown to suppress the tumorigenicity of certain tumor cells. In the present study, we have used a semiquantitative immunohistochemical approach to evaluate the extent of nuclear localization of β-catenin in human colonic adenocarcinomas and adenomas and compared it to the distribution of plakoglobin in the same tissues. We show that β-catenin accumulates in the nuclei of the epithelium of primary and metastatic colonic adenocarcinoma as well as in colonic adenomas. In contrast, nuclear plakoglobin levels in these tissues were low, even compared to those found in epithelial cells of normal colon. These results support the view that the increase in β-catenin levels in colon cancer cells occurs early in the tumorigenic process, leading to its nuclear localization, not only in invasive adenocarcinoma, but also in colonic adenoma with mild dysplasia.
1. Ben-Ze'ev A, Rodriguez-Fernandez YL, Gluck U, Salomon D, Geiger B. Changes in adhesion plaque protein levels regulate cell motility and tumorigenicity. In Estes IE, Higgins PY (eds): Actin biology biochemistry and cell biology. New York, Plenum Press, pp. 147-157, 1994
2.
2. Ben-Ze'ev A. The cytoskeleton of cancer cells. Biochim Biophys Acta780:197-212, 1985
3.
3. Lafrenie RM, Buchanan MR, Orr FW. Adhesion molecules and their role in cancer metastasis. Cell Biophys23:3-89, 1993
4.
4. Giancotti FG, Mainiero F. Integrin-mediated adhesion and signaling in tumorigenesis. Biochim Biophys Acta1198:17-61, 1994
5.
5. Birchmeier W, Hulsken J, Behrens J. Adherens junction proteins in tumor progression. Cancer Surv24:129-140, 1995
6.
6. Kemperman II, Driessens MH, La Riviere GAM, Meijne AM, Roos E. Adhesion mechanisms in liver metastasis formation. Cancer Surv24:67-79, 1995
7.
7. Kinch MS, Burridge K. Altered adhesions in rastransformed breast epithelial cells. Cancer Metastasis Rev14:173-189, 1995
8.
8. Lifschitz-Mercer B, Czernobilsky B, Feldberg E, Geiger B. Expression of the adherens junction protein vinculin in human basal and squamous cell tumors: Relationship to invasiveness and metastatic potential. Hum Pathol28:1230-1236, 1997
9.
9. Pasquale EB, Maher PA, Singer SJ. Talin is phosphorylated on tyrosine in chicken embryo fibroblasts transformed by Rous Sarcome Virus. Proc Natl Acad Sci83:5507-5511, 1986
10.
10. Volberg T, Geiger B, Dror R, Zick Y. Modulation of intercellular adherens-type junctions and tyrosine phosphorylation of their components in RSV-transformed cultured chick lens cells. Cell Regul2:105-120, 1991
11.
11. Gumbiner BM. Carcinogenesis: A balance between β-catenin and APC. Curr Biol7:R443-R446, 1997
12.
12. Peifer M. β-Catenin as oncogene: The smoking gun. Science27:1752-1753, 1997
13.
13. Kemler R. From cadherins to catenins: Cytoplasmic protein interactions and regulation of cell adhesion. Trends Genetics9:317-321, 1993
14.
14. Geiger B, Yehuda-Levenberg S, Bershadsky AD. Molecular interactions in the submembrane plaque of cell-cell and cell-matrix adhesions. Acta Anat154:46-62, 1995
15.
15. De Leeuw WJF, Berx G, Vos CBJ, Peterse JL, Van de Vijver MJ, Litvinov S, van Roy F, Cornelisse CJ, Cleton-Janssen AM. Simultaneous loss of E-cadherin and catenins in invasive lobular breast cancer, and lobular carcinoma in situ. J Pathol183:404-411, 1997
16.
16. Fujimoto J, Ichigo S, Hirose R, Sakaguchi H, Tamaya T. Expression of E-cadherin and alphaand beta-catenin mRNAs ovarian cancer. Cancer Lett19:207-212, 1997
17.
17. Hao X, Palazzo JP, Ilyas M, Tomlinson I, Talbot IC. Reduced expression of molecules of the cadherin/catenin complex in the transition from colorectal adenoma to carcinoma. Anticancer Res17:2241-2247, 1997
18.
18. Krishnadath KK, Tilanus HW, van Blankenstein M, Hop WC, Kremers ED, Dinjens WN, Bosman FT. Reduced expression of the cadherin-catenin complex in oesophageal adenocarcinoma correlates with poor prognosis. J Pathol182:331-338, 1997
19.
19. Valizadeh A, Karayiannakis AJ, el-Hariry I, Kmiot W, Pignatteli M. Expression of E-cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120) in colorectal polyps. Am J Pathol150:1077-1084, 1997
20.
20. Bagutti C, Speight PM, Watt FM. Comparison of integrin, cadherin, and catenin expression in squamous cell carcinomas of the oral cavity. J Pathol186:8-16, 1998
21.
21. Noriko H, Toshitaka N, Akira A, Kondon Y, Nagao K. Expression of E-cadherin, β-catenin and γ-catenin in bronchioloalveolar carcinoma and conventional pulmonary adenocarcinoma: An immunohostochemical study. Mod Pathol11: 1039-1045, 1998
22.
22. Sanders DS, Bruton R, Darnton SJ, Casson AG, Hanson I, Williams HK, Janausky Y. Sequential changes in cadherin-catenin expression associated with the progression and heterogeneity of primary oesophageal squamous carcinoma. Int J Cancer18:573-579, 1998
23.
23. Takayama T, Shiozaki H, Doki Y, Oka H, Inove M, Yamamoto M, Tamura S, Shibamoto F, Otp F, Monden M. Aberrant expression and phosphorylation of β-catenin in human colorectal cancer. Br J Cancer77:605-613, 1998
24.
24. Bankfalvi A, Terpe H-J, Breukelmann D, Bier B, Rempe D, Pschadka G, Krech RR, Lelle RJ, Boecker W. Immunophenotypic and prognostic analysis of E-cadherin and β-catenin expression during breast carcinogenesis and tumor progression: A comparative study with CD44. Histopathology34:25-34, 1999
25.
25. Inomata M, Ochiai A, Akimoto S, Kitano S, Hirohashji S. Saturation of β-catenin expression in colonic epithelial cells of familial adenomatous polyposis patients. Cancer Research56:2213-2217, 1996
26.
26. Korinek V, Barker N, Morin PJ, van Wichen D, de Weger R, Kinzler KW, Vogelstein B, Clevers H. Constitutive transcriptional activation by a β-catenin-Tcf complex in APC-colon carcinoma. Science275:1784-1787, 1997
27.
27. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler K W. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science275:1787-1790, 1997
28.
28. Brabletz T, Herrmann K, Jung A, Faller G, Kirchner T. Expression of nuclear β-catenin and c-myc is correlated with tumor size but not with proliferative activity of colorectal adenomas. Am J Pathol156:865-870, 2000
29.
29. Kirchner T, Brabletz T. Patterning and nuclear β-catenin expression in the colonic adenoma-carcinoma sequence. Am J Pathol157:1113-1121, 2000
30.
30. Rubinfeld B, Robbins P, El-Gamil M, Albert I, Porfiro E, Polakis P. Stabilization of β-catenin by genetic defects in melanoma cell lines. Science275: 1790-1792, 1997
31.
31. Ben-Ze'ev A. Cytoskeletal and adhesion proteins as tumor suppressors. Curr Opin Cell Biol9:99-108, 1997
32.
32. Ben-Ze'ev A, Geiger B. Differential molecular interactions of β-catenin and plakoglobin in adhesion, signaling and cancer. Curr Opin Cell Biol10:629-639, 1998
33.
33. Behrens J, von Kries JP, Kuhl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W. Functional interaction of β-catenin with the transcription factor LEF-1. Nature382:638-642, 1996
34.
34. Huber O, Korn R, McLaughlin J, Ohsugi M, Herrmann BG, Kemler R. Nuclear localization of β-catenin by interaction with transcription factor LEF-1. Mech Dev59:3-11, 1996
35.
35. Molenaar M, van de Wetering M, Oosterwegel M, Korineki V, Roose J, Destnee O, Petersonmadura J, Godsave S, Clevers H. XTcf-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell86:391-399, 1996
36.
36. Cowin P, Kapprell HP, Franke WW, Tankon J, Hynes RO. Plakoglobin: A protein common to different kinds of intercellular adhering junctions. Cell46:1063-1073, 1986
37.
37. Simcha I, Geiger B, Yehuda-Levenberg S, Salomon D, Ben-Ze'ev A. Suppression of tumorigenicity by plakoglobin: An augmenting effect of N-cadherin. J Cell Biol133:199-209, 1996
38.
38. Munemitsu SI, Albert B, Souza B, Rubinfeld B, 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
39.
39. He TC, Sparks AB, Rago C, Hermeking H, Zaivel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW. Identification of c-MYC as a target of the APC pathway. Science281:1509-1512, 1998
40.
40. Shtutman M, Zhurinsky J, Albanese C, D'Amico M, Pestell R, Ben-Ze'ev A. Cyclin DI is a target of the β-catenin/LEF-1 pathway. Proc Natl Acad Sci USA96:5522-5527, 1999
41.
41. Polakis P. The adenomatous polyposis coli (APC) tumor suppressor. Biochim Biophys Acta1332: F127-F147, 1997
42.
42. Cooper HS: Benign epithelial polyps of the intestines, in Ming S-C, Goldman H (eds): Pathology of the gastrointestinal tract, 2nd ed., Williams and Wilkins, Baltimore, pp. 883-884, 1998
43.
43. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, van Tuinen P, Ledbetter DH, Barker DF, Nakamura Y, White R, Vogelstein B. Chromosome 17 deletions and p53 gene mutations in colorectal carcinoma. Science244:217-221, 1989
44.
44. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell61:759-767, 1990
45.
45. Kinzler KW, Nibert MC, Vogelstein B, Bryan TM, Levy DB, Smith KJ, Preisinger AC, Hamilton SR, Hedge P, Markham A, Carlson M, Joslyn G, Groden Y, White R, Miki Y, Miyoshi Y, Nishisho I, Nakamura Y. Identification of a gene located at chromosome 5q 21 that is mutated in colorectal cancers. Science251:1366-1370, 1991
46.
46. Salomon D, Sacco PA, Guha Roy S, Simcha I, Johnson KR, Wheelock, MJ, Ben-Ze'ev A. Regulation of β-catenin levels and localization by overexpression of plakoglobin and inhibition of the ubiquitin-proteasome system. J Cell Biol139:1325-1335, 1997
47.
47. Sadot E, Simcha I, Shtutman M, Ben-Ze'ev A, Geiger B. Inhibition of β-catenin-mediated transactivation by cadherin derivatives. Proc Natl Acad Sci USA95:15339-15344, 1998
48.
48. Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell87:159-170, 1996
49.
49. Cuoello C, Margio C, Correa P. Atypia in adenomas in three populations with different risks for large bowel cancer. Cali, Sao Paulo and New Orleans, Natl Cancer Inst53:171-173, 1979
50.
50. Muto T, Kamiya Y, Sawada T, Konishi F, Sugihara K, Kubota Y, Adachi M, Azawa S, Saito Y, Morioka Y, Tanprayoon T. Small flat adenomas of the large bowel with special reference to its clinicopathological features. Dis Colon Rectum28:847-851, 1985
51.
51. Cooper HS. Benign epithelial polyps of the intestines, in Ming S-C, Goldman H (eds). Pathology of the gastrointestinal tract, 2nd ed, Williams & Wilkins, Baltimore, pp. 845-849, 1998
52.
52. Bansal P, Sonnenberg A. Risk factors of colorectal cancer in inflammatory bowel disease. Am J Gastroenterol91:44-48, 1996
53.
53. Walsh SV, Loda M, Torres CM, Antonioli D, Odze RD. p53 and β-catenin expression in chronic ulcerative colitis-associated polypoid dysplasia and sporadic adenomas. Am J Surg Pathol23:963-969, 1999
