Vitamin D reseptör ekspresyonunun kolorektal kanserlerde evre ile ilişkisi ve prognoz üzerine etkisi
Giriş ve Amaç: Kolorektal kanser hücrelerinde vitamin D reseptör eks-presyonunun tespiti ve bu reseptör ekspresyon derecesi ile kolorektal kanser prognoz ve evresinin ilişkisi olup olmadığını tespit etmektir. Gereç ve Yöntem: Çalışmaya 2003-2009 tarihleri arasında Ankara Üniversitesi Tıp Fakültesi Genel Cerrahi Bölümünde opere olmuş, Ankara Üniversitesi Tıp Fakültesi Patoloji Bölümünde kolon ve rektum kanseri tanısı konu-lup medikal tedavisi aynı üniversitenin Tıbbi Onkoloji Bölümünce yapılan hastalar dahil edilmiştir. Vitamin D reseptörlerinin değerlendirilmesi için seçilen olguların hematoksilen ve eozin kesitleri yeniden değerlendirildi. Vitamin D reseptör tayininde 9A7 immünoglobulin G2b monoklonal anti-kor boyaması kullanıldı. Bulgular: Çalışmaya 64’ü (%55.7) erkek ve 51’i (%44.3) kadın olmak üzere toplam 115 hasta alındı. Vitamin D reseptörü pozitif olan hastalarda genel sağ kalım istatistiksel olarak anlamlı olmasa da reseptör negatif olanlara göre daha iyi bulunmuştur. Vitamin D resep-tör pozitif olanlarda medyan sağ kalıma ulaşılamamıştır. 5 yıllık sağ kalım %69.4 oranında saptanmıştır. Vitamin D reseptör negatif olanlarda med-yan sağ kalım 60 ay olarak saptanmıştır. 5 yıllık sağ kalım %32 oranında bulunmuştur. Vitamin D reseptör negatif olanlarda 5 yıllık hastalıksız sağ kalım %56.8 bulunurken, vitamin D reseptör pozitif olanlarda hastalıksız sağ kalım %43.3 bulunmuştur. Vitamin D reseptör pozitif ve negatif olanlar arasında hastalıksız sağ kalım açısından istatiksel olarak anlamlı fark saptanmamıştır (p: 0.053). Sonuç: Vitamin D reseptör ekspresyonu-nun kolorektal kanser prognozu üzerine olan etkisinin tek başına anlamlı olmadığı saptanmıştır. Reseptör ekspresyonu dışında reseptör polimor-fizminin ve reseptörün etkilediği yolaklarda rol oynayan mutasyonların da prognozu belirlemede etkili olabileceği kanısına varılmıştır.
Expression of vitamin D receptor in colorectal cancer staging and its effects on prognosis
Background and Aims: The aim of the study was to evaluate the effects of vitamin D receptor expression on the prognosis and stag-ing of colorectal cancer. Materials and Methods: Pathological speci-mens of 115 patients diagnosed with colorectal cancer were analyzed. Perinuclear vitamin D receptors were immunohistochemically analyzed with 9A7 IgG2b monoclonal antibody. Results: Vitamin D receptor positivity, serosa infiltration, metastatic lymph node involvement, re-lapse period, and staging relationship was not statistically significant. Survival was found to be better in vitamin D receptor-positive patients than in vitamin D receptor-negative patients; however, the results were not statistically significant. Vitamin D receptor-positive patients could not achieve median survival, but their 5-year survival was found to be 43.3%. Vitamin D receptor-negative patients achieved a median sur-vival of 60 months, and the 5-year survival was 56.8%. Survival with-out disease was not significant based on vitamin D receptor positivity. There was no significant difference in disease-free survival between vitamin D receptor-positive and vitamin D receptor-negative patients (p = 0.053). Conclusion: Colorectal cancer prognosis was not affected with vitamin D receptor expression alone. Besides vitamin D receptor expression, receptor polymorphisms and mutations at the routes of re-ceptor affection and investigation of other factors would be beneficial.
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- 1. Simboli-Campbell M, Gagnon A, Franks DJ, Welsh J. 1,25-Dihy-droxyvitamin D3 translocates protein kinase C beta to nucleus and enhances plasma membrane association of protein kinase C alpha in renal epithelial cells. J Biol Chem 1994;269:3257-64.
- 2. Diaz GD, Paraskeva Ci Thomas MG, Binderup L, Hague A. Apopto-sis is induced by the active metabolite of vitamin D3 and its ana-logue EB1089 in colorectal adenoma and carcinoma cells: possible implications for prevention and therapy. Cancer Res 2000;60:2304-12.
- 3. Haussler MR, Whitfield GK, Haussler CA, et al. The nuclear vita-min D receptor: biological and molecular regulatory properties revealed. J Bone Miner Res 1998;13:325-49.
- 4. Barsony J, Pike W, DeLuca HF, Marx SJ. Immunocytology with microwave-fixed fibroblasts shows 1 alpha,25-dihydroxyvitamin D3-dependent rapid and estrogen-dependent slow reorganization of vitamin D receptors. J Cell Biol 1990;111:2385-95.
- 5. Fedirko V, Bostiak RM, Long Q, et al. Effects of supplemental vi-tamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial. Cancer Epidemiol Biomarkers Prev 2010;19: 280-91.
- 6. Freedman LP. Transcriptional targets of the vitamin D3 receptor-me-diating cell cycle arrest and differentiation. J Nutr 1999;129(2S Suppl):581S-586S.
- 7. Zehnder D, Bland R, Williams MC, et al. Extrarenal expression of 25-hydroxyvitamin d(3)-1 alpha-hydroxylase. J Clin Endocrinol Me-tab 2001;86:888-94.
- 8. Hsu JY, Feldman D, McNeal JE, Peehl DM. Reduced 1alpha-hy-droxylase activity in human prostate cancer cells correlates with decreased susceptibility to 25-hydroxyvitamin D3-induced growth inhibition. Cancer Res 2001;61:2852-6.
- 9. Friedrich M, Diesing D, Cordes T, et al. Analysis of 25-hydroxyvita-min D3-1alpha-hydroxylase in normal and malignant breast tissue. Anticancer Res 2006;26:2615-20.
- 10. Matusiak D, Murillo G, Carroll RE, Mehta RG, Benya RV. Expression of vitamin D receptor and 25-hydroxyvitamin D3-1{alpha}-hydroxy-lase in normal and malignant human colon. Cancer Epidemiol Bio-markers Prev 2005;14:2370-6.
- 11. Lointier P, Wargovich MJ, Saez S, et al. The role of vitamin D3 in the proliferation of a human colon cancer cell line in vitro. Antican-cer Res 1987;7:817-21.
- 12. Shabahang M, Buras RR, Davodi F, et al. 1,25-Dihydroxyvitamin D3 receptor as a marker of human colon carcinoma cell line differenti-ation and growth inhibition. Cancer Res 1993;53:3712-8.
- 13. Sheinin Y, Kaserer K, Wrba F, et al. In situ mRNA hybridization anal-ysis and immunolocalization of the vitamin D receptor in normal and carcinomatous human colonic mucosa: relation to epidermal growth factor receptor expression. Virchows Arch 2000;437:501-7.
- 14. Elloul S, Elstrand MB, Nesland JM, et al. Snail, Slug, and Smad-inter-acting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 2005;103:1631-43.
- 15. Otani T, Iwasaki M, Sasazuki S; Japan Public Health Center-Based Prospective Study Group. Plasma vitamin D and risk of colorectal cancer: the Japan Public Health Center-Based Prospective Study. Br J Cancer 2007;97:446-51.
- 16. Grau MV, Baron JA, Sandler RS, et al. Vitamin D, calcium supple-mentation, and colorectal adenomas: results of a randomized trial. J Natl Cancer Inst 2003;95:1765-71.
- 17. Wactawski-Wnde J, Kotchen JM, Anderson GL, Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006;354:684-96.
- 18. Garland CF, Comstock GW, Garland FC, et al. Serum 25-hydroxyvi-tamin D and colon cancer: eight-year prospective study. Lancet 1989;2:1176-8.
- 19. Cross HS, Pavelka M, Slavik J, Peterlik M. Growth control of human colon cancer cells by vitamin D and calcium in vitro. J Natl Cancer Inst 1992;84:1355-7.
- 20. Hulla W, Kallay E, Krugluger W, Peterlik M, Cross HS. Growth control of human colon-adenocarcinoma-derived Caco-2 cells by vitamin-D compounds and extracellular calcium in vitro: relation to c-myc-oncogene and vitamin-D-receptor expression. Int J Cancer 1995;62:711-6.
- 21. Matusiak D, Murillo G, Carroll RE, Mehta RG, Benya RV. Expression of vitamin D receptor and 25-hydroxyvitamin D3-1{alpha}-hydroxy-lase in normal and malignant human colon. Cancer Epidemiol Bio-markers Prev 2005;14:2370-6.
- 22. Deeb KK, Trump DL, Johnson CS. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat Rev Cancer 2007;7:684-700.
- 23. Zhang Y, Zhang J, Studzinski GP. AKT pathway is activated by 1, 25-dihydroxyvitamin D3 and participates in its anti-apoptotic ef-fect and cell cycle control in differentiating HL60 cells. Cell Cycle 2006;5:447-51.
- 24. Hughes PJ, Brown G. 1Alpha,25-dihydroxyvitamin D3-mediated stimulation of steroid sulphatase activity in myeloid leukaemic cell lines requires VDRnuc-mediated activation of the RAS/RAF/ERK-MAP kinase signalling pathway. J Cell Biochem 2006;98:590-617.
- 25. Kure S, Nosho K, Baba Y, et al. Vitamin D receptor expression is associated with PIK3CA and KRAS mutations in colorectal cancer. Cancer Epidemiol Biomarkers Prev 2009;18:2765-72.
26. Thomas MG, Sylvester PA, Newcomb P, Longman RJ. Vitamin D re-ceptor expression in colorectal cancer. J Clin Pathol 1999;52:181-3.
- 27. Meggouh F, Lointier P, Saez S. Sex steroid and 1,25-dihydroxy vita-min D3 receptors in human colorectal adenocarcinoma and normal mucosa. Cancer Res 1991;5:1227-33.
- 28. Kane KF, Langman MJ, Williams GR. 1,25-Dihydroxyvitamin D3 and retinoid X receptor expression in human colorectal neoplasms. Gut 1995;36:255-8.
- 29. Meggouh F, Lointier P, Pezet D, Saez S. Evidence of 1,25-dihy-droxyvitamin D3-receptors in human digestive mucosa and car-cinoma tissue taken at different levels of digestive tract, in 152 patients. J Steroid Biochem 1990;36:143-7.
- 30. Lointier P, Meggough F, Dechelotte P, et al. 1,25-Dihydroxyvita-min D3 receptors and human colon adenocarcinoma. Br J Surg 1991;78:435-9.
- 31. Welsh J. Vitamin D and breast cancer:insights from animal models. Am J Clin Nutr 2004;80(6 Suppl):1721S-4S.
- 32. Hines SL1, Jorn HK, Thompson KM, Larson JM. Breast cancer survi-vors and vitamin D: A review. Nutrition 2010;26:255-62.
- 33. Heist RS, Zhou W, Wang Z, et al. Circulating 25-hydroxyvitamin D, VDR polymorphisms, and survival in advanced non–small-cell lung cancer. J Clin Oncol 2008;26:5596-602.
- 34. Blomberg Jensen M, Andersen CB, Nielsen JE, et al. Expression of the vitamin D receptor, 25-hydroxylases, 1-hydroxylase and 24-hy-droxylase in the human kidney and renal clear cell cancer. J Steroid Biochem Mol Biol 2010;121:376-82.
- 35. Cross HS, Bises G, Lechner D, Manhardt T, Kállay E. The Vitamin D endocrine system of the gut--its possible role in colorectal cancer prevention. J Steroid Biochem Mol Biol 2005;97:121-8.
- 36. Byers SW, Rowlands T, Beildeck M, Bong YS. Mechanism of action of vitamin D and the vitamin D receptor in colorectal cancer preven-tion and treatment. Rev Endocr Metab Disord. 2012;13:31-8.