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Comparison of Beta-catenin with TGF-beta1, HIF-1alpha and Patients’ Disease-free Survival in Human Colorectal Cancer

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Pathology & Oncology Research

Abstract

Beta-catenin accumulation is suppressed by TGF-beta1 (transforming growth factor beta1) in intestinal epithelium suggesting negative feedback between these two factors. Besides that, beta-catenin interacts with HIF-1alpha (hypoxia-inducible factor-1alpha) at the promoter region of HIF-1 target genes. Our study was aimed at comparison of beta-catenin with HIF-1alpha, TGF-beta1, Ki67 and survival of sporadic colorectal cancer patients. Expressions of beta-catenin, TGF-beta1, HIF-1alpha, Ki67 were evaluated in triads of specimens of each primary tumor of 72 sporadic colorectal cancers with immunohistochemistry due to limited availability of tissue material. Disease-free survival was analyzed in case of all 100 beta-catenin stained tumors, in 85 cancers stained for HIF-1 and in 72 neoplasms with TGFbeta1 staining. Beta-catenin, TGF-beta1 and HIF-1alpha accumulated in 72 colorectal cancer cells. Beta-catenin correlated both with HIF-1alpha and TGF-beta1 in all colorectal cancers (p < 0.009, r = 0.307 and p = 0.003, r = 0.342, respectively) and in subgroups of different clinico-pathological profile. Beta-catenin failed to correlate with Ki67. In case of beta-catenin, TGF-beta1 and HIF-1alpha, disease-free survival curves failed to show any statistically significant differences between groups of marker negative tumors, cancers with low expression and neoplasms with higher protein expression. Positive correlations between beta-catenin and TGF-beta1 may indicate ineffective attempts of TGF-beta1 to reduce intracellular level of beta-catenin in colorectal cancer. Associations between beta-catenin and HIF-1alpha reflect previously detected interactions between HIF-1alpha with beta-catenin and are confirmative for presence of such reactions in human colorectal cancer.

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References

  1. Wong NA, Pignatelli M (2002) Beta-catenin-a linchpin in colorectal carcinogenesis? Am J Pathol 160:389–401

    CAS  PubMed  Google Scholar 

  2. Lüchtenborg M, Weijenberg MP, Wark PA, Saritas AM, Roemen GM, van Muijen GN, de Bruïne AP, van den Brandt PA, de Goeij AF (2005) Mutations in APC, CTNNB1 and K-ras genes and expression of hMLH1 in sporadic colorectal carcinomas from the Netherlands Cohort Study. BMC Cancer 5:160

    Article  PubMed  Google Scholar 

  3. Sulkowska M, Wincewicz A, Sulkowski S, Koda M, Kanczuga-Koda L (2009) Relations of TGF-beta1 with HIF-1alpha, GLUT-1 and longer survival of colorectal cancer patients. Pathology Jan 13:1–7. [Epub ahead of print]

    Google Scholar 

  4. Xu J, Attisano L (2000) Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 97:4820–4825

    Article  CAS  PubMed  Google Scholar 

  5. Li F, Cao Y, Townsend CM Jr, Ko TC (2005) TGF-beta signaling in colon cancer cells. World J Surg 29:306–311

    Article  PubMed  Google Scholar 

  6. Bacman D, Merkel S, Croner R, Papadopoulos T, Brueckl W, Dimmler A (2007) TGF-beta receptor 2 downregulation in tumour-associated stroma worsens prognosis and high-grade tumours show more tumour-associated macrophages and lower TGF-beta1 expression in colon carcinoma: a retrospective study. BMC Cancer 7:156

    Article  PubMed  Google Scholar 

  7. Giles RH, Lolkema MP, Snijckers CM, Belderbos M, van der Groep P, Mans DA, van Beest M, van Noort M, Goldschmeding R, van Diest PJ, Clevers H, Voest EE (2006) Interplay between VHL/HIF1alpha and Wnt/beta-catenin pathways during colorectal tumorigenesis. Oncogene 25:3065–3070

    Article  CAS  PubMed  Google Scholar 

  8. de la Roche M, Worm J, Bienz M (2008) The function of BCL9 in Wnt/beta-catenin signaling and colorectal cancer cells. BMC Cancer 8:199

    Article  PubMed  Google Scholar 

  9. Lim JH, Chun YS, Park JW (2008) Hypoxia-inducible factor-1alpha obstructs a Wnt signaling pathway by inhibiting the hARD1-mediated activation of beta-catenin. Cancer Res 68:5177–5184

    Article  CAS  PubMed  Google Scholar 

  10. Li LN, Zhang HD, Yuan SJ, Tian ZY, Wang L, Sun ZX (2007) Artesunate attenuates the growth of human colorectal carcinoma and inhibits hyperactive Wnt/beta-catenin pathway. Int J Cancer 121:1360–1365

    Article  CAS  PubMed  Google Scholar 

  11. Kaidi A, Williams AC, Paraskeva C (2007) Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 9:210–217

    Article  CAS  PubMed  Google Scholar 

  12. Wincewicz A, Sulkowska M, Koda M, Sulkowski S (2007) Cumulative expression of HIF-1-alpha, Bax, Bcl-xL and P53 in human colorectal cancer. Pathology 39:334–338

    Article  CAS  PubMed  Google Scholar 

  13. Wincewicz A, Sulkowska M, Koda M, Sulkowski S (2007) Clinicopathological significance and linkage of the distribution of HIF-1alpha and GLUT-1 in human primary colorectal cancer. Pathol Oncol Res 13:15–20

    Article  CAS  PubMed  Google Scholar 

  14. Wang H, Promkan M, Liu G, Chakrabarty S (2008) Switch of transforming growth factor beta function from tumor suppression to stimulation in adenomatous polyposis coli (APC) knocked-down human colon carcinoma cells. Cancer Lett 272:253–259

    Article  CAS  PubMed  Google Scholar 

  15. Wang H, Rajan S, Liu G, Chakrabarty S (2008) Transforming growth factor beta suppresses beta-catenin/Wnt signaling and stimulates an adhesion response in human colon carcinoma cells in a Smad4/DPC4 independent manner. Cancer Lett 264:281–287

    Article  CAS  PubMed  Google Scholar 

  16. Lambie DL, Brown IS (2008) Multinucleate epithelial change in colorectal hyperplastic polyps: a review of 27 cases. J Clin Pathol 61:611–614

    Article  CAS  PubMed  Google Scholar 

  17. Settakorn J, Kaewpila N, Burns GF, Leong AS (2005) FAT, E-cadherin, beta catenin, HER 2/neu, Ki67 immuno-expression, and histological grade in intrahepatic cholangiocarcinoma. J Clin Pathol 58:1249–1254

    Article  CAS  PubMed  Google Scholar 

  18. Pirinen RT, Hirvikoski P, Johansson RT, Hollmén S, Kosma VM (2001) Reduced expression of alpha-catenin, beta-catenin, and gamma-catenin is associated with high cell proliferative activity and poor differentiation in non-small cell lung cancer. J Clin Pathol 54:391–395

    Article  CAS  PubMed  Google Scholar 

  19. Wong SC, Chan AT, Chan JK, Lo YM (2006) Nuclear beta-catenin and Ki-67 expression in choriocarcinoma and its pre-malignant form. J Clin Pathol 59:387–392

    Article  CAS  PubMed  Google Scholar 

  20. Takeda K, Kinoshita I, Shimizu Y, Ohba Y, Itoh T, Matsuno Y, Shichinohe T, Dosaka-Akita H (2008) Clinicopathological significance of expression of p-c-Jun, TCF4 and beta-catenin in colorectal tumors. BMC Cancer 8:328

    Article  PubMed  Google Scholar 

  21. Tien YW, Jeng YM, Hu RH, Chang KJ, Hsu SM, Lee PH (2004) Intravasation-related metastatic factors in colorectal cancer. Tumour Biol 25:48–55

    Article  CAS  PubMed  Google Scholar 

  22. Pećina-Slaus N, Niku Eva-Martić T, Beros V et al (2007) Genetic alterations of E-cadherin and beta-catenin in germinoma and teratoma: report of two central nervous system cases. Pathol Oncol Res 13:370–374

    Article  PubMed  Google Scholar 

  23. Kabukcuoglu F, Kabukcuoglu Y, Tanik C et al (2008) Breast carcinoma metastasis in recurrent myxoid liposarcoma. Pathol Oncol Res

  24. Horst D, Kriegl L, Engel J et al (2009) CD133 and nuclear beta-catenin: the marker combination to detect high risk cases of low stage colorectal cancer. Eur J Cancer

  25. Horst D, Reu S, Kriegl L et al (2009) The intratumoral distribution of nuclear beta-catenin is a prognostic marker in colon cancer. Cancer 115:2063–2070

    Article  PubMed  Google Scholar 

  26. Bondi J, Bukholm G, Nesland JM, Bakka A, Bukholm IR (2006) An increase in the number of adhesion proteins with altered expression is associated with an increased risk of cancer death for colon carcinoma patients. Int J Colorectal Dis 21:231–237

    Article  PubMed  Google Scholar 

  27. Canavese G, Bernardi A, Candelaresi G, Lovadina P, Amerio S, Rossetti V, Rabagliati C, Berardengo E (2007) Expression of the E-cadherin-catenins complex in sentinel node is related to tumor morphology but not to spread to nonsentinel nodes. Pathol Res Pract 203:517–523

    Article  PubMed  Google Scholar 

  28. Stewart CJ, Crook ML, Leung YC, Platten M (2009) Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands. Mod Pathol, Mar 6. [Epub ahead of print]

  29. Nagayama S, Yamada E, Kohno Y, Aoyama T, Fukukawa C, Kubo H, Watanabe G, Katagiri T, Nakamura Y, Sakai Y, Toguchida J (2009) Inverse correlation of the up-regulation of FZD10 expression and the activation of beta-catenin in synchronous colorectal tumors. Cancer Sci 100:405–412

    Article  CAS  PubMed  Google Scholar 

  30. Mees ST, Mennigen R, Spieker T, Rijcken E, Senninger N, Haier J, Bruewer M (2009) Expression of tight and adherens junction proteins in ulcerative colitis associated colorectal carcinoma: upregulation of claudin-1, claudin-3, claudin-4, and beta-catenin. Int J Colorectal Dis 24:361–368

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Andrzej Wincewicz would like to address the Foundation for Polish Science his thanks for awarding him a scholarship START.

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Wincewicz, A., Koda, M., Sulkowski, S. et al. Comparison of Beta-catenin with TGF-beta1, HIF-1alpha and Patients’ Disease-free Survival in Human Colorectal Cancer. Pathol. Oncol. Res. 16, 311–318 (2010). https://doi.org/10.1007/s12253-009-9217-2

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  • DOI: https://doi.org/10.1007/s12253-009-9217-2

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