Polimorfismo do Receptor de Vitamina D (VDR) e atividade antiproliferativa do colecalciferol em células cancerígenas

Autores

DOI:

https://doi.org/10.33448/rsd-v9i12.10810

Palavras-chave:

Câncer de Mama; Glioblastoma; Receptor de vitamina D; PCR-RFLP; SNP; Tumor cerebral.

Resumo

A vitamina D (VD) é um hormônio esteróide com múltiplas funções biológicas no corpo e sua atividade requer a ligação ao receptor denominado VDR. Os polimorfismos do VDR parecem estar envolvidos no desenvolvimento de vários tipos de cânceres. Aqui, realizamos a genotipagem de dois polimorfismos VDR (Fok I e Taq I) em linhagens celulares de câncer de mama MCF-7 e glioblastoma U87-MG (GBM) e investigamos o efeito antiproliferativo do colecalciferol análogo da VD. Os polimorfismos foram identificados por PCR-RFLP e o efeito da VD foi determinado por viabilidade e ensaios clonogênicos. A VD inibiu o crescimento de ambas as células tumorais in vitro. As células MCF-7 foram mais sensíveis do que as células U87-MG em concentrações que variam de 0,1 nM a 1000 nM. Os mesmos pares de primers usados para amplificação por PCR do gene VDR em MCF-7 não conseguiram amplificar um fragmento de tamanho esperado na linha de células U87-MG. Os polimorfismos VDR Fok I e Taq I em células MCF-7 de câncer de mama foram caracterizados como FF (CC) e TT, respectivamente. A ausência de amplificação do fragmento do gene VDR no U87-MG sugere um possível rearranjo cromossômico e/ou prejuízo da expressão gênica do VDR que poderia interferir na sensibilidade dessa linhagem celular à VD.

Referências

Ahmed, H., Makonnen, E., Fotoohi, A., Yimer, G., Seifu, D., Assefa, M., et al. (2019). Vitamin D Status and Association of VDR Genetic Polymorphism to Risk of Breast Cancer in Ethiopia. Nutrients, 11, 2, 289. doi: 10.3390/nu11020289.

Alimirah, F., Peng, X., Murillo, G., Mehta, R. G. (2011). Functional Significance of Vitamin D Receptor FokI Polymorphism in Human Breast Cancer Cells, Plos one, e16024.

Anic, G. M. (2012). An exploratory analysis of common genetic variants in the vitamin D pathway including genome-wide associated variants in relation to glioma risk and outcome. Cancer Causes Control, 23, 9, 1443–1449. doi: 10.1371/journal.pone.0016024.

Bao, B-Y.,Yeh, S-D., & Lee, Y-F. (2006). 1a,25-dihydroxyvitamin D3 inhibits prostate cancer cell invasion via modulationof selective proteases (2006). Carcinogenesis, 27, 32–42. doi: 10.1093/carcin/bgi170.

Boneti, R. S., & Fagundes, R. B. Vitamin D and Cancer (2013). Revista da AMRIG, 57 (1):71-77. Retrieved from: https://revistapresenca.celsolisboa.edu.br/index.php/numer ohum/article/view/122.

Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin. 68 (6), 394–424. doi:10.3322/caac.21492.

Chen, W. Y., Berone-Johnson, E. R., Hunter, D. J., Willett, W. C., Hankinson, S. E. (2005). Association between polymorphism in the vitamin D receptor and breast cancer risk. Cancer Epidemiol Biomarkers Prev, 14, 2335–2339. doi: 10.1158/1055-9965.EPI-05-0283.

Chen, Y. (2018). Vitamin D receptor suppresses proliferation and metastasis in renal cell carcinoma cell lines via regulating the expression of the epithelial Ca2+ channel TRPV5. PLoS One, 13, e0195844. doi: 10.1371/journal.pone.0195844.

DeBerardinis, A. M., Lemieux, S., Hadden, M. K. Analogues of the Inhoffen-Lythgoe diol with antiproliferative activity (2013). Bioorg Med Chem Lett. 19, 5367-5370. doi: 10.1016/j.bmcl.2013.07.054.

Dolecek, T. A., et al., (2012). CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro-oncology, 14 (suppl 5), v1-v49. doi: 10.1093/neuonc/nos218.

Evans, M. A., Kim, H. A., Ling, Y. H., Uong, S., Vinh, A., De Silva, T. M., et al. (2018). Vitamin D3 Supplementation Reduces Subsequent Brain Injury and Inflammation Associated with Ischemic Stroke. Neuro Molecular Med, 20 (1):147-159. doi: 10.1007/s12017-018-8484-z.

Ferronato, M. J., Alonso, E. N., Salomón, D. G., Fermento, M. E., Gandini, N. A., Quevedo, M. A., et al. (2018). Antitumoral effects of the alkynylphosphonate analogue of calcitriol EM1 on glioblastoma multiforme cells. J Steroid Biochem Mol Biol. 178, 22-35. doi: 10.1016/j.jsbmb.2017.10.019.

Franken, N. A. P., Rodermond, H. M., Stap, J., Haveman, J., & van Bree, C. Clonogenic assay of cells in vitro. Nature Protocols; 2006, 1 n 5, doi: 10.1038/nprot.2006.339. doi: 10.1038/nprot.2006.339.

Garland, C. F., Garland, F. C., Gorham, E. D., Lipkin, M., Newmark, H., Mohr, S. B., et al. (2006). The Role of Vitamin D in Cancer Prevention. American Journal of Public Health, 96 (2): 252–261. doi: 10.2105/AJPH.2004.045260

Giovannucci, E. (2005). The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control, 16 (2):83-95. doi: 10.1007/s10552-004-1661-

Gocek, E., & Studzinski, G. P. (2009). Vitamin D and differentiation in câncer. Crit Rev Clin Lab Sci., (4). doi:10.1080/10408360902982128.

Gross, C., Krishnan, A. V., Malloy, P. J., Eccleshall, T. R., Zhao, X. Y., Feldman, D. (1998). The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants. J Bone Miner Res, 13 (11), 1691–1699. doi:10.1359/jbmr.1998.13.11.1691.

Grundmann, M., Haidar, M., Placzko, S., Niendorf, R., Darashchonak, N., Hubel, C. A., & Von Versen-Höynck, F. (2012). Vitamin D Improves the Angiogenic Properties of Endothelial Progenitor Cells. Am J Physiol Cell Physiol. 303 (9), C954–C962. doi: 10.1152/ajpcell.00030.2012.

Guy, M., Lowe, L. C., Bretherton-Watt, D., Mansi, J. L., Peckitt, C., et al. (2004). Vitamin D receptor gene polymorphisms and breast cancer risk. Clin Cancer Res, 10, 5472–5481. DOI: 10.1158/1078-0432.CCR-04-0206.

Hardiman, G., Savage, S. J., Hazard, E. S., Wilson, R. C., Courtney, S. M., Smith, M. T., et al. (2016) Systems analysis of the prostate transcriptome in African–American men compared with European–American men. Pharmacogenomics, 17(10), 1129–1143. doi: 10.2217/pgs-2016-0025.

Koh, C. M (2013). Isolation of Genomic DNA from Mammalian Cells. Methods in Enzymology, 529. doi: 10.1016/B978-0-12-418687-3.00013-6.

Lu, D., Jing, L., Zhang, S. (2016). Vitamin D Receptor Polymorphism and Breast Cancer Risk a Meta-Analysis (2016). Medicine, 95. doi: 0.1097/MD.0000000000003535.

McCullough, M. L., Stevens, V. L., Diver, W. R., Feigelson, H. S., Rodriguez, C., et al. (2007). Vitamin D pathway gene polymorphisms, diet, and risk of postmenopausal breast cancer: a nested case-control study. Breast Cancer Res, 9: R9. doi:10.1186/bcr1642.

Mousa, N., Helena, T., Robert, S., Barbora, C. (2018). Vitamin D supplementation for improvement of chronic low-grade inflammation in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Nutr Rer, 76, 380 – 394. doi: 0.1093/nutrit/nux077.

Nilufer, G., et al (2016). The role of vitamin D receptor gene polymorphisms in Turkish infants with urolithiasis. Renal Failure, 545–551. doi: 10.3109/0886022X.2016.1148557.

Pan, L., Matloob, A. F., Du, J., Pan, H., Dong, Z., Zhao, J., et al (2009). Vitamin D stimulates apoptosis in gastric cancer cells in synergy with trichostatin A ⁄sodium butyrate-induced and 5-aza-2¢-deoxycytidine-induced PTEN upregulation. FEBS Journal, 277, 989–999. doi:10.1111/j.1742-4658.2009.07542.x.

Rai, V., Abdo, J., Agrawal, S., & Agrawal, D. K. (2017). Vitamin D Receptor Polymorphism and Cancer: An Update. Anticancer research, 3991-4003, doi: 10.21873/anticanres.11784. doi: 10.21873/anticanres.11784.

Raza, S., Dhasmana, A., Bhatt, M. L. B., Lohani, M., Arif, J. M. (2019). Molecular Mechanism of Cancer Susceptibility Associated withFok1 Single Nucleotide Polymorphism of VDR in Relation to Breast Cancer. Asian Pac J Cancer Prev, 20, (1). doi:10.31557/APJCP.2019.20.1.199.

Salomon, D. G., Fermento, M. E., Gandini, N. A., Ferronato, M. J., Arevalo, J., et al. (2014). Vitamin D receptor expression is associated with improved overall survival in human glioblastoma multiforme. J Neuro oncol, 1, 49-60. doi: 10.1007/s11060-014-1416-3.

Saracligil, B., Ozturk, B., Unlu, A., Abusoglu, S., Tekin, G. (2017). The effect of vitamin D on MCF-7 breast cancer cell metabolism. Bratisl Med J, 118, 2 101 – 106.

Sinotte, M., Rousseau, F., Ayotte, P., Dewailly, E., Diorio, C., et al. (2008). Vitamin D receptor polymorphisms (FokI, BsmI) and breast cancer risk: association replication in two case-control studies within French Canadian population. Endocr Relat Cancer, 15, 975–983. doi: 10.4149/BLL_2017_021.

Strober, W. Trypan Blue Exclusion Test of Cell Viability (2015). Curr Protoc Immuno. 111: A3.B.1–A3.B.3. doi: 10.1002/0471142735.ima03bs111.

Toptaş, B., Kafadar, A. M., Cacina, C., Turan, S., Yurdum, L. M., Yiğitbaşı, N., et al. (2013). The vitamin D receptor (VDR) gene polymorphisms in Turkish brain cancer patients. Biomed Res Int, 295791. doi:10.1155/2013/2957

Vargas-Rondón, N., Villegas, V. E., & Rondón-Lagos, M. (2018). The Role of Chromosomal Instability in Cancer and Therapeutic Responses. Cancers, 10, 4. doi: 10.3390/c ancers10010004.

Wang, Y., Zhu, J., DeLuca, H. F. (2012). Where is the vitamin D receptor? Arch Biochem Biophys, 523 (1):123–133. doi:10.1016/j.abb.2012.04.001.

Yaylım-Eraltan, I., Arzu Ergen, H., Arıkan, S., Okay, E., Ozturk, O., & Bayrak, S. (2007). Investigation of the VDR gene polymorphisms association with susceptibility to colorectal cancer. Cell Biochem Funct, 731-737. doi: 10.1002/cbf.1386.

Yuan, L., Jiang, R., Yang, Y., Ding, S., & Deng, H. (2012). 1,25-Dihydroxyvitamin D3 inhibits growth of the breast cancer cell line MCF-7 and down regulates cytochrome P4501B1through the COX-2/PGE2 pathway. Oncology reports, 2131-2137. doi: 10.3892/or.2012.2031.

Zerwekh, E. J. (2008) Blood biomarkers of vitamin D status. Am J Clin Nutr, 87 (4), 1087S-91S. doi:10.1093/ajcn/87.4.108.

Zheng, W., Tayyari, F., Gowda, G. A., Raftery, D., McLamore, E. S., Shi, J., et al. (2013). 1, 25 Dihydroxyvitamin D Regulation of Glucose Metabolism in Harvey-ras Transformed MCF10A Human Breast Epithelial Cells. J Steroid Biochem Mol Biol, 2013138, 81–89. doi: 10.1016/j.jsbmb.2013.03.012.

Zou, J., Landy, H., Feun, L., Xu, R., Lampidis, T., Wu, C. J., et al. (2000). Correlation of a unique 220-kDa protein with vitamin D sensitivity in glioma cells Biochemical Pharmacology, 60(9). doi: 10.1016/S0006-2952(00)00438-X.

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14/12/2020

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LOPES, A. R.; FELIPE, V. G.; SANTOS, R. G. dos; SANTOS, W. G. dos. Polimorfismo do Receptor de Vitamina D (VDR) e atividade antiproliferativa do colecalciferol em células cancerígenas. Research, Society and Development, [S. l.], v. 9, n. 12, p. e8991210810, 2020. DOI: 10.33448/rsd-v9i12.10810. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/10810. Acesso em: 25 nov. 2024.

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Ciências da Saúde