Kolon adenokarsinomlarında ve adenomatöz poliplerinde Beta-Catenin ve Sox2 ekspresyonu ve klinikopatolojik parametreler ile ilişkileri

Abstract

Amaç: β-katenin ve Sox-2’nin kolonun adenomatöz polipleri ve adenokarsinomunda immünohistokimyasal ekspresyonunun araştırılması, adenom-karsinom sekansında bu belirteçlerin yeri ve etkisinin değerlendirilmesidir. Yöntem: 56 düşük dereceli displazi içeren tübüler adenom(DDDTA), 53 yüksek dereceli displazi içeren tübüler adenom (YDDTA), 44 tübülovillöz adenom (TVA), 29 villöz adenom (VA) ve 60 kolon adenokarsinomu çalışma kapsamına alındı. β-katenin için nükleer ve sitoplazmik, Sox-2 için nükleer boyanma değerlendirildi ve semikantitatif skorlama yapıldı. Bulguların gruplar arasında ve klinikopatolojik parametrelerle ilişkisi değerlendirildi. Bulgular: Nükleer β-katenin ekspresyonu adenokarsinomda poliplere nazaran anlamlı olarak fazla saptandı. Poliplerde ise VA ile YDDTA arasında VA lehine; TVA ile YDDTA ve TVA ile DDDTA grupları arasında TVA lehine farklıdır. Sitoplazmik β-katenin, adenokarsinom ile VA, TVA, YDDTA ve DDDTA grupları arasında adenokarsinom lehine; VA ile TV, YDDTA ve DDDTA grupları arasında VA lehine; TVA ile YDDTA grupları arasında TVA lehine ve YDDTA ile DDDTA arasında YDDTA lehine istatistiksel olarak anlamlı farklılık bulunmuştur. Sonuç: Gruplardaki β-katenin sonuçları literatür ile uyumludur. Sox2 ekspresyonu malign potansiyeli destekler niteliktedir. Adenom-karsinom sekansında Sox2’nin etkisinin ayrıntılı açıklanabilmesi için moleküler çalışmalar ile desteklenen geniş serili araştırmalara gereksinim vardır.

Keywords

• kolon
• adenomatöz polip
• adenokarsinom
• beta katenin
• sox2

The expression of Beta-Catenin and Sox2 in adenocarcinoma and adenomatous polyps of the colon and their association with clinicopathological parameters

Abstract

Objective: Our aim was to investigate the immunohistochemical expression of β-catenin and Sox-2 in adenomatous polyps and adenocarcinoma of colon and also to evaluate the effects of these markers in adenoma-carcinoma sequence and their association with clinicopathological parameters. Methods: Fifty-six tubular adenomas with low grade dysplasia (TALGD), 53 tubular adenomas with high grade dysplasia (TAHGD), 44 tubulovillous adenomas (TVA), 29 villous adenomas (VA) and 60 adenocarcinomas were included in the study. The nuclear staining of Sox2 was evaluated as well as both nuclear and cytoplasmic stainings of β-catenin. A semiquantitative scoring was performed. The results were compared between the groups and the relationship of the results with clinicopathological parameters was evaluated. Results: Nuclear and cytoplasmic β-catenin expressions of the adenocarcinomas were higher than polyps. The expressions in the VA and TVA polyp groups were higher than the expressions in TAHGD and TALGD, respectively. Membranous β-catenin expression in the adenocarcinoma was higher than the polyps except VA. The evaluation between polyp groups with respect to membranous β-catenin staining revealed a statistically significantly difference in favor of VA compared with TVA, TAHGD and TALGD; in favor of TAHGD compared with TVA, in favor of TVA compared with TALGD while it was found statistically significantly higher in TAHGD than TALGD. Conclusion: The results regarding β-catenin expression of the polyp groups were consistent with the literature. There was a positive correlation between β-catenin expression (nuclear and cytoplasmic) and malignancy. High Sox2 expressions were found correlated with malignancy potential. Large sampling size investigations to be supported by further molecular studies are needed to clarify the effect of Sox2 expression in the sequence of adenoma-carcinoma comprehensively.

Keywords

• colon
• adenomatous polyp
• adenocarcinoma
• beta catenin

References

1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383:1490-1502. https://doi.org/10.1016/S0140-6736(13)61649-9
2. Fenoglio-Preiser CM, Noffsinger AE, Stemmermann GN, Lantz PE, Isaacson PG. Epitelial neoplasms of the colon. In: Fenoglio-Preiser CM, Noffsinger AE, Stemmermann GN, Lantz PE, Isaacson PG, editors. Gastrointestinaly Pathology an Atlas and Text. 3th ed. Philadelphia: Lippincott Williams&Wilkins;2008:899-1036.
3. Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 9th Ed. Philadelphia: Elsevier Saunders; 2015.
4. Kolligs FT, Bommer G, Göke B. Wnt/Beta-Catenin/Tcf Signaling: A Critical Pathway in Gastrointestinal Tumorigenesis. Digestion. 2002;66(3):131-144. https://doi.org/10.1159/000066755.
5. Ong CW, Kim LG, Kong HH, Low LY, Iacopetta B, Soong R, et al. CD133 expression predicts for non-response to chemotherapy in colorectal cancer. Mod Pathol. 2010;23(3):450-457. https://doi.org/10.1038/modpathol.2009.181
6. Liu H, Du L, Wen Z, Yang Y, Li J, Dong Z, et al. Sex determining region Y-box 2 inhibits the proliferation of colorectal adenocarcinoma cells through the mTOR signaling pathway. Int J Mol Med. 2013;32(1):59-66. https://doi.org/10.3892/ijmm.2013.1354
7. Neumann J, Bahr F, Horst D, Kriegl L, Engel J, Luque RM, et al. Sox2 expression correlates with lymph-node metastases and distant spread in right-sided colon cancer. BMC Cancer. 2011;11:518. https://doi.org/10.1186/1471-2407-11-518
8. Amersi F, Agustin M, Ko CY. Colorectal cancer: Epidemiology, Risk Factors and Health Services. Clin Colon Rectal Surg. 2005;18(3):133-140. https://doi.org/10.1055/s-2005-916274

9. Silva SM, Rosa VF, Santos AC, Almeida RM, Oliveira PG, Sousa JB. Influence of patient age and colorectal polyp size on histopathology findings. Arq Bras Cir Dig. 2014;27(2):109-113. https://doi.org/10.1590/s0102-67202014000200006
10. de Oliveira AM, Anapaz V, Lourenço L, Graça Rodrigues C, Folgado Alberto S, Martins A, et al. Is there a proximal shift in the distribution of colorectal adenomas? United European Gastroenterol J. 2015;3(4):353-7. https://doi.org/10.1177/2050640615577534
11. Herter P, Kuhnen C, Müller K-M, Wittinghofer A, Müller O. Intracellular distribution of B-catenin in colorectal adenomas, carcinomas and Peutz-Jeghers polyps. J Cancer Res Clin Oncol. 1999:125:297-304. https://doi.org/10.1007/s004320050277
12. Iwamoto M, Ahnen DJ, Franklin WA, Maltzman TH. Expression of B-catenin and full-length APC protein in normal and neoplastic tissues. Carcinogenesis. 2000;21:1935-1940 https://doi.org/10.1093/carcin/21.11.1935
13. Nazemalhosseini Mojarad E, Kashfi SM, Mirtalebi H, Almasi S, Chaleshi V, Kishani Farahani R, et al. Prognostic Significance of Nuclear Β-Catenin Expression in Patients with Colorectal Cancer from Iran. Iran Red Crescent Med. 2015;22;17(7):e22324 https://doi.org/10.5812/ircmj.22324v2.
14. Hlubek F, Brabletz T, Budczies J, Pfeiffer S, Jung A, Kirchner T. Heterogeneous expression of Wnt/B-catenin target genes within colorectal cancer. Int J Cancer. 2007;121:1941-1948 https://doi.org/10.1002/ijc.22916
15. Lugli A, Zlobec I, Minoo P, Baker K, Tornillo L, Terracciano L, et al. Prognostic significance of the Wnt signalling pathway molecules APC, beta-catenin and E-cadherin in colorectal cancer: A tissue microarray-based analysis. Histopathology. 2007:50(4):453-64. https://doi.org/10.1111/j.1365-2559.2007.02620.x.
16. Günther K, Brabletz T, Kraus C, Dworak O, Reymond MA, Jung A, et al. Predictive value of nuclear beta-catenin expression for the occurrence of distant metastases in rectal cancer. Dis Colon Rectum. 1998;41:1256–1261. https://doi.org/10.1007/BF02258226.
17. Chung GG, Provost E, Kielhorn EP, Charette LA, Smith BL, Rimm DL. Tissue microarray analysis of beta-catenin in colorectal cancer shows nuclear phospho-beta-catenin is associated with a better prognosis. Clin. Cancer Res. 2001;7:4013–20.
18. Bowles J, Schepers G, Koopman P. Phylogeny of the Sox family of developmental transcription factors based on sequence and structural indicators. Dev Biol. 2000;227:239-255. https://doi.org/10.1006/dbio.2000.9883.
19. Kormish JD, Sinner D, Zorn AM. Interactions between SOX factors and Wnt/B-catenin signaling in development and disease. Dev Dyn. 2010;239(1):56-68. https://doi.org/10.1002/dvdy.22046
20. Que J, Okubo T, Goldenring JR, Nam KT, Kurotani R, Morrisey EE, et al. Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm. Development. 2007;134(13):2521-31. https://doi.org/10.1242/dev.003855
21. Sinner D, Kordich JJ, Spence JR, Opoka R, Rankin S, Lin SC, et al. Sox17 and Sox4 differentially regulate beta-catenin/T-cell factor activity and proliferation of colon carcinoma cells. Mol Cell Biol. 2007;27(22):7802-7815.https://doi.org/10.1128/MCB.02179-06
22. Bastide P, Darido C, Pannequin J, Kist R, Robine S, Marty-Double C, et al. Sox9 regulates cell proliferation and is required for Paneth cell differentiation in the intestinal epithelium. J Cell Biol. 2007;178(4):635-648. https://doi.org/10.1083/jcb.200704152
23. Gracz AD, Magness ST. Sry-box (Sox) transcription factors in gasrtointestinal physiology and disease. Am J Physiol Gastrointest Liver Physiol. 2011;300(4):503-515. https://doi.org/10.1152/ajpgi.00489.2010
24. Li XL, Eishi Y, Bai YQ, Sakai H, Akiyama Y, Tani M, et al. Expression of the SRY related HMG box protein Sox2 in human gastric carcinoma. Int J Oncol. 2004;24:257-263
25. Fang X, Yu W, Li L, Shao J, Zhao N, Chen Q, et al. ChIP-seq and functional analysis of the Sox2 gene in colorectal cancers. OMICS. 2010;14(4);369-384. https://doi.org/10.1089/omi.2010.0053
26. Saigusa S, Tanaka K, Toiyama Y, Yokoe T, Okugawa Y, Ioue Y, et al. Correlation of CD133, OCT4 and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol. 2009;16:3488-3498.https://doi.org/10.1245/s10434-009-0617-z.
27. Watanabe H, Ma Q, Peng S, Adelmant G, Swain D, Song W, et al. SOX2 and P63 colocalize at genetic loci in squamous cell carcinomas. J Clin Invest. 2014;124(4):1636-1645. https://doi.org/10.1172/JCI71545
28. Park ET, Gum JR, Kakar S, Kwon SW, Deng G, Kim YS. Aberrant expression of Sox2 upregulates MUC5AC gastric foveolar mucin in mucinous cancers of the colorectum and related lesions. Int J Cancer. 2008;122(6):1253-60. https://doi.org/10.1002/ijc.23225