Molecular & Cellular Toxicology

The Korean Society of Toxicogenomics and Toxicoproteomics (대한독성유전 단백체학회)
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Immunohistochemical Analysis of TBX3 and $\beta$-catenin in Gastric Cancers

  • Song, Jae-Hwi (Department of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Yoon, Jung-Hwan (Department of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Kang, Young-Hwi (Department of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Cao, Zhang (Department of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Nam, Suk-Woo (Department of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Lee, Jung-Young (Department of Pathology, College of Medicine, The Catholic University of Korea) ;
  • Park, Won-Sang (Department of Pathology, College of Medicine, The Catholic University of Korea)
  • Published : 2009.12.31
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Abstract

TBX3 has demonstrated oncogenic activity as a downstream target of the Wnt/$\beta$-catenin signaling pathway. In this study, the aim was to determine whether overexpression of the TBX3 protein is involved in the development and/or progression of gastric cancers. We analyzed the expression pattern of the TBX3 and $\beta$-catenin proteins in a series of 186 sporadic gastric cancers. Altered expression of the TBX3 and $\beta$-catenin proteins was observed in 54 (29.0%) and 48 (25.8%) of the 186 gastric cancers. Statistically, overexpression of the TBX3 and $\beta$-catenin proteins was not associated with the clinical and pathological parameters studied including: histological type, tumor location, tumor size, and the 5-year survival (P>0.05). However, TBX3 overexpression was closely associated with lymph node metastasis and aberrant $\beta$-catenin expression (P<0.05). In addition, overexpression of the TBX3 protein was confirmed by Western blot analysis of primary gastric cancer tissues and cell lines. These data suggest that TBX3 overexpression may play a role in the development and progression of sporadic gastric cancers.

Keywords

References

  1. Jemal, A. et al. Cancer statistics, 2008. CA Cancer J Clin 58:71-96 (2008) https://doi.org/10.3322/CA.2007.0010
  2. Shin, H. R., Jung, K. W., Won, Y. J. & Park, J. G. 139 KCCR-affiliated Hospitals, 2002 Annual Report of the Korea Central Cancer Registry: Based on Registered Data from 139 Hospitals. Cancer Research and Treatment 36:103-114 (2004) https://doi.org/10.4143/crt.2004.36.2.103
  3. Peifer, M. & Polakis, P. Wnt signaling in oncogenesis and embryogenesis-a look outside the nucleus. Science 287:1606-1609 (2000) https://doi.org/10.1126/science.287.5458.1606
  4. Polakis, P. The many ways of Wnt in cancer. Curr Opin Genet Dev 17:45-51 (2007) https://doi.org/10.1016/j.gde.2006.12.007
  5. Lustig, B. & Behrens, J. The Wnt signaling pathway and its role in tumor development. J Cancer Res Clin Oncol 129:199-221 (2003) https://doi.org/10.1007/s00432-003-0431-0
  6. Park, W. S. et al. Frequent somatic mutations of the beta-catenin gene in intestinal-type gastric cancer. Cancer Res 59:4257-4260 (1999)
  7. Ebert, M. P. et al. Increased beta-catenin mRNA levels and mutational alterations of the APC and betacatenin gene are present in intestinal-type gastric cancer. Carcinogenesis 23:87-91 (2002) https://doi.org/10.1093/carcin/23.1.87
  8. Kolligs, F. T., Bommer, G. & Goke, B. Wnt/beta-catenin/ tcf signaling: a critical pathway in gastrointestinal tumorigenesis. Digestion 66:131-144 (2002) https://doi.org/10.1159/000066755
  9. Muller, W., Noguchi, T., Wirtz, H. C., Hommel, G. & Gabbert, H. E. Expression of cell-cycle regulatory proteins cyclin D1, cyclin E, and their inhibitor p21 WAF1/CIP1 in gastric cancer. J Pathol 189:186-193 (1999) https://doi.org/10.1002/(SICI)1096-9896(199910)189:2<186::AID-PATH418>3.0.CO;2-L
  10. Sanz-Ortega, J. et al. Comparative study of tumor angiogenesis and immunohistochemistry for p53, c- ErbB2, c-myc and EGFr as prognostic factors in gastric cancer. Histol Histopathol 15:455-462 (2000)
  11. Kispert, A. & Hermann, B. G. The Brachyury gene encodes a novel DNA binding protein. EMBO J 12: 4898-4909 (1993)
  12. Bamshad, M. et al. Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome. Nat Genet 16:311-315 (1997) https://doi.org/10.1038/ng0797-311
  13. Carlson, H., Ota, S., Song, Y., Chen, Y. & Hurlin, P. J. Tbx3 impinges on the p53 pathway to suppress apoptosis, facilitate cell transformation and block myogenic differentiation. Oncogene 21:3827-3835 (2002) https://doi.org/10.1038/sj.onc.1205476
  14. Ito, A., Asamoto, M., Hokaiwado, N., Takahashi, S. & Shirai, T. Tbx3 expression is related to apoptosis in rat bladder both hyperplastic epithelial cells and carcinoma cells. Cancer Lett 219:105-112 (2005) https://doi.org/10.1016/j.canlet.2004.07.051
  15. Renard, C. A. et al. Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer. Cancer Res 67:901-910 (2007) https://doi.org/10.1158/0008-5472.CAN-06-2344
  16. Yuasa, Y. Control of gut differentiation and intestinaltype gastric carcinogenesis. Nat Rev Cancer 3:592-600 (2003) https://doi.org/10.1038/nrc1141
  17. Franco, A. T. et al. Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci 102: 10646-10651 (2005) https://doi.org/10.1073/pnas.0504927102
  18. Naiche, L. A., Harrelson, Z., Kelly, R. G. & Papaioannou, V. E. T-box genes in vertebrate development. Annu Rev Genet 39:219-239 (2005) https://doi.org/10.1146/annurev.genet.39.073003.105925
  19. Lingbeek, M. E., Jacobs, J. J. & van Lohuizen, M. The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. J Biol Chem 277:26120-26127 (2002) https://doi.org/10.1074/jbc.M200403200
  20. Prince, S., Carreira, S., Vance, K. W., Brahams, A. & Goding, C. R. Tbx2 directly represses the expression of the p21(WAF1) cyclin-dependent kinase inhibitor. Cancer Res 64:1669-1674 (2004) https://doi.org/10.1158/0008-5472.CAN-03-3286
  21. Brummelkamp, T. R. et al. TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence. J Biol Chem 277: 6567-6572 (2002) https://doi.org/10.1074/jbc.M110492200
  22. Lomnytska, M., Dubrovska, A., Hellman, U., Volodko, N. & Souchelnytskyi, S. Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients. Int J Cancer 118:412-421 (2006) https://doi.org/10.1002/ijc.21332
  23. Lyng, H. et al. Gene expressions and copy numbers associated with metastatic phenotypes of uterine cervical cancer. BMC Genomics 7:268 (2006) https://doi.org/10.1186/1471-2164-7-268
  24. Gulmann, C. et al. Adenomatous polyposis coli gene, beta-catenin, and E-cadherin expression in proximal and distal gastric cancers and precursor lesions: an immunohistochemical study using tissue microarrays. Appl Immunohistochem Mol Morphol 11:230-237 (2003)
  25. Fan, W., Huang, X., Chen, C., Gray, J. & Huang, T. TBX3 and its isoform TBX3+2a are functionally distinctive in inhibition of senescence and are overexpressed in a subset of breast cancer cell lines. Cancer Res 64:5132-5139 (2004) https://doi.org/10.1158/0008-5472.CAN-04-0615
  26. Rodriguez, M., Aladowicz, E., Lanfrancone, L. & Goding, C. R. Tbx3 represses E-cadherin expression and enhances melanoma invasiveness. Cancer Res 68:7872-7881 (2008) https://doi.org/10.1158/0008-5472.CAN-08-0301
  27. Kononen, J. et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844-847 (1998) https://doi.org/10.1038/nm0798-844
  28. Matsumoto, K., Shariat, S. F., Ayala, G. E., Rauen, K. A. & Lerner. S. P. Loss of coxsackie and adenovirus receptor expression is associated with features of aggressive bladder cancer. Urology 66:441-446 (2005) https://doi.org/10.1016/j.urology.2005.02.033