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DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi

Year 2014, Volume 36, Issue 2, 03.07.2015

Abstract

ÖZET:Akciğer kanseri, akciğer dokusundaki hücrelerin kontrolsüz olarak çoğalması ile meydana gelir ve kanser kaynaklı ölümlerin en yaygın nedenidir. En önemli nedenleri uzun süreli sigara dumanı maruziyeti, genetik faktörler, radon gazı ve asbest maruziyetidir. miRNA’lar kendi nükleotid dizilerinin tamamlayıcısı olan hedef mRNA’lara bağlanıp translasyonel baskılama veya mRNA yıkımı ile transkripsiyon sonrası gen ekspresyonunun düzenlenmesini gerçekleştirirler. Çeşitli çalışmalarda malignant tümörlerin gelişimi ve ilerlemesi ile miRNA ekspresyon düzensizliklerinin ilişkili olduğu, miRNA'ların onkogen veya tümör süpresör (baskılayıcı) olarak hareket edebileceği belirtilmiştir. Ayrıca tümör baskılayıcı genlerin downregülasyonu ve CpG dinükleotidlerindeki promotör hipermetilasyonu tümörogenezis için önemli bir mekanizmadır. Bir diğer epigenetik düzenleme olan miRNA’ların, genlerin promotör bölgelerindeki anormal metilasyon ve histon modifikasyonları gibi epigenetik mekanizmaları düzenleyebileceği bildirilmiştir. Bu amaçla biz de güncel veri tabanları ile DNMT3b ve MBD1’i hedefleyen 2 miRNA genine ait iki SNP belirleyerek bu SNP’lerin akciğer kanseri ile ilişkisini araştırmayı amaçladık. Gereç ve Yöntem: Çalışmamıza 90 sağlıklı kontrol birey ve 90 akciğer kanseri hastası dahil edildi (onay no: 2012/45). EDTA’lı tüplere alınan kan örneklerinden DNA izole edildi ve bu DNA’lar Sequenom MassARRAY sistemi ile genotiplendirildi. Hastaların genetik varyasyon tipleri ve demografik özellikleri uygun istatistiksel yöntemler ile değerlendirildi. Bulgular: DNMT3b’yi hedefleyen miR339 geni rs72631831 varyantı tüm bireyler için atasal GG genotipine, MBD1’i hedefleyen miR15b geni rs146020563 varyantı için tüm bireyler atasal AA genotipine sahip olarak belirlendi. Sonuç: Araştırmamızda rs72631831 ve rs146020563 varyasyonları ile akciğer kanseri arasında ilişki bulunamamıştır ancak araştırmamız DNA metilasyon mekanizmasını hedefleyen miRNA gen varyantlarının da fonksiyonel karakterizasyonunun yapıldığı ilk çalışma olması nedeniyle önemlidir.

ANAHTAR KELİMELER: Akciğer Kanseri, DNA metilasyonu, DNA Metiltransferaz-3b, Metil Bağlayan Protein-1, miRNA, SNP.


SUMMARY: Aim: Lung cancer (LC) is a disease that develops by uncontrolled cell growth in tissues of the lung and the most common cause of cancer-related death. Most significant risk factors for LC are tobacco smoke, genetic factors, radon gas and asbestos.miRNAs bind target mRNAs which are complementary to their sequences and post-transcriptionally regulate gene expression through translational repression or mRNA degradation. Several observations link dysregulation of miRNA expression to the development and progression of tumors and miRNAs can act as oncogenes or tumor suppressors. The hypermethylation of CpG-dinucleotides in the promoter of genes and downregulation of tumor suppressors are important for tumorogenesis. It has been reported that being a type of epigenetic modifier, miRNAs, may regulate epigenetic mechanism including abnormal methylation of the promoter regions or histone modifications.For this purpose, we determined the SNPs on two miRNA genes targeting DNMT3b and MBD1 with current databases and aimed to investigate the association of these SNPs with lung cancer. Material and methods:  Accordingly, 90-controls and 90-patients were included in our study (approval no: 2012/45). DNAs were isolated from blood samples and these DNA samples were genotyped by Sequenom MassARRAY System. The demographic characteristics of patients and types of genetic variation were evaluated by appropriate statistical methods. Results: It was determined that all individuals have the ancestral GG and AA genotype for rs72631831 variant of miR339 targeting DNMT3b and rs146020563 variant of miR15b targeting MBD1, respectively.Conclusion: We found no association between rs72631831 and rs146020563 variation with lung cancer,  however our research is important due to being the first study to indicate the functional characterization of gene variants of miRNA genes targeting DNA methylation.

KEY WORDS: Lung cancer, DNA methylation, DNA methyltranferas-3b, Methyl Binding Protein-1, miRNA, SNP.

 


References

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  • Metintaş, M. (2005). Asbest temasına bağlı plevral patolojiler ve mezotelyoma. Turkiye Klinikleri Journal of Internal Medical Sciences 1, 96-110.
  • Topu, Z. Ülger, F. and Numanoğlu, N. (2004). Ailesel kanser hikayesi ve akciğer kanseri. Tüberküloz ve Toraks Dergisi. 52,130-136.
  • Onay, H. (2006). Konvansiyonel renal hücreli kanser oluşumunda etkili olan genlerin metilasyon durumunun araştırılması. Doktora Tezi, Ege Üniversitesi İzmir.
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  • Weber, B. Stresemann, C. Brueckner, B. and Lyko, F. (2007). Methylation of human microRNA genes in normal and neoplastic cells. Cell Cycle-Landes Bioscience. 6, 1001.
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  • Shenfield, G.M. (2004). Genetic polymorphisms, drug metabolism and drug concentrations. The Clinical BiochemistReviews/Australian Association of Clinical Biochemists.25, 203-206.
  • Vignal, A. Milan, D. SanCristobal, M. and Eggen, A. (2002). A review on SNP and other types of molecular markers and their use in animal genetics.Genetics Selection, evolution : GSE 34, 275-305.
  • Ekmekçi, A. Konaç, E. and Önen, H.İ. (2008). Gen polimorfizmi ve kansere yatkınlık. Gen. 21, 282-295.
  • http://www.ncbi.nlm.nih.gov/gene/
  • Spitz, M.R. Hong, W.K. Amos, C.I. Wu, X. Schabath, M.B. Dong, Q. Shete, S. and Etzel, C.J. (2007). A Risk Model for Prediction of Lung Cancer. Journal of the National Cancer Institute. 99, 715-726.
  • Tammemagi, C.M. Pinsky, P.F. Caporaso, N.E. Kvale, P.A. Hocking, W.G. Church, T.R. Riley, T.L. Commins, J. Oken, M.M. and Berg, C.D. (2011). Lung cancer risk prediction: prostate, lung, colorectal and ovarian cancer screening trial models and validation. Journal of The National Cancer Institute. 103, 1058-1068.
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Year 2014, Volume 36, Issue 2, 03.07.2015

Abstract

References

  • Aydıner, A. (2007). Akciğer kanseri: tanı-tedavi-takip.(Nobel Tıp Kitabevleri).
  • Ak, G. and Metintaş, M. (2014). Akciğer kanseri, tanı ve destek tedavisinde aile hekimi.(Ankara: Rotatıp Kitabevi).
  • Metintaş, M. (2005). Asbest temasına bağlı plevral patolojiler ve mezotelyoma. Turkiye Klinikleri Journal of Internal Medical Sciences 1, 96-110.
  • Topu, Z. Ülger, F. and Numanoğlu, N. (2004). Ailesel kanser hikayesi ve akciğer kanseri. Tüberküloz ve Toraks Dergisi. 52,130-136.
  • Onay, H. (2006). Konvansiyonel renal hücreli kanser oluşumunda etkili olan genlerin metilasyon durumunun araştırılması. Doktora Tezi, Ege Üniversitesi İzmir.
  • Yaykaşlı, K.O. Hatipoğlu, Ö.F. Ertuğrul, K. and Yaykaşlı, E. (2012). Epigenetik mekanizmalar ve kanser. Dicle Tıp Dergisi 14, 58-68.
  • Bora, G. and Yurter, H. (2007). Epigenetik hastalıklar ve tedavi yaklaşımları. Hacettepe Tıp Dergisi. 38, 48-54.
  • Novik, K. Nimmrich, I. Genc, B. Maier, S. Piepenbrock, C. Olek, A. and Beck, S. (2002). Epigenomics: genome-wide study of methylation phenomena. Current Issues in Molecular Biology 4, 111-128
  • Lüleyap, Ü.H. (2008). Moleküler genetiğin esasları. (Ankara: Nobel Tıp Kitabevleri).
  • Çelik, S. (2007). Kronik miyeloid lösemili hastalarda dap kinaz geninin metilasyon analizleri. Yüksek Lisans Tezi, Ankara Üniversitesi, Biyoteknoloji Enstitüsü, Ankara.
  • Varol , N. (2007). Akut Lösemilerde Socs-1 Geninin Metilasyon Analizi. Yüksek Lisans Tezi, Ankara Üniversitesi, Sağlık Bilimleri Enstitüsü Ankara.
  • Kaymak, A. (2012). Farklı kanserlerin hücre hatlarında demetilasyon oluşturulması ile tümör süpresör ve stamp ailesi gen ifade değişikliklerinin incelenmesi. Yüksek Lisans Tezi, Ege Üniversitesi Sağlık Bilimleri Enstitüsü, İzmir.
  • Garzon, R. Liu, S. Fabbri, M. Liu, Z. Heaphy, C.E. Callegari, E. Schwind, S. Pang, J.Yu, J. and Muthusamy, N. (2009). MicroRNA-29b induces global DNA hypomethylation and tumor suppressor gene reexpression in acute myeloid leukemia by targeting directly DNMT3A and 3B and indirectly DNMT1. Blood 113, 6411-6418.
  • Tang, M. Xu, W. Wang, Q. Xiao, W. and Xu, R. (2009). Potential of DNMT and its epigenetic regulation for lung cancer therapy. Current Genomics. 10, 336.
  • Belinsky, S.A. Klinge, D.M. Stidley, C.A. Issa, J.P. Herman, J.G. March, T.H. and Baylin, S.B. (2003). Inhibition of DNA methylation and histone deacetylation prevents murine lung cancer. Cancer Research. 63, 7089-7093.
  • Lin, X. and Nelson, W.G. (2003). Methyl-CpG-binding domain protein-2 mediates transcriptional repression associated with hypermethylated GSTP1 CpG islands in MCF-7 breast cancer cells. Cancer Research. 63, 498-504.
  • Ballestar, E. Paz, M.F. Valle, L. Wei, S. Fraga, M.F. Espada, J. Cigudosa, J.C. Huang, T.H.M. and Esteller, M. (2003). Methyl‐CpG binding proteins identify novel sites of epigenetic inactivation in human cancer. The EMBO Journal. 22, 6335-6345.
  • Kanai, Y. Ushijima, S. Kondo, Y. Nakanishi, Y. and Hirohashi, S. (2001). DNA methyltransferase expression and DNA methylation of CPG islands and peri‐centromeric satellite regions in human colorectal and stomach cancers. International Journal Of Cancer. 91, 205-212.
  • Bandres, E. Agirre, X. Bitarte, N. Ramirez, N. Zarate, R. Roman‐Gomez, J. Prosper, F. and Garcia‐Foncillas, J. (2009). Epigenetic regulation of microRNA expression in colorectal cancer. International Journal Of Cancer. 125, 2737-2743.
  • Lehmann, U. Hasemeier, B. Christgen, M. Muller, M. Romermann, D. Langer, F. and Kreipe, H. (2008). Epigenetic inactivation of microRNA gene hsamir-9-1 in human breast cancer. J Pathol.214, 17-24.
  • Lujambio, A. Ropero, S. Ballestar, E. Fraga, M.F. Cerrato, C. Setién, F. Casado, S. Suarez-Gauthier, A. Sanchez-Cespedes, M. and Gitt, A. (2007). Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Research. 67, 1424-1429.
  • Saito, Y. Liang, G. Egger, G. Friedman, J.M. Chuang, J.C. Coetzee, G.A. and Jones, P.A. (2006). Specific activation of microRNA-127 with downregulation of the proto-oncogene BCL6 by chromatin-modifying drugs in human cancer cells. Cancer Cell. 9, 435-443.
  • Saydam, F. Değirmenci, İ. and Güneş, H.V. (2011). MikroRNA’lar ve kanser Dicle Tıp Dergisi. 38, 113-120.
  • Han, L. Witmer, P.D.W. Casey, E. Valle, D. and Sukumar, S. (2007). DNA methylation regulates MicroRNA expression. Cancer Biology and Therapy 6, 1284.
  • Iorio, M.V. Piovan, C. and Croce, C.M. (2010). Interplay between microRNAs and the epigenetic machinery: an intricate network. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms 1799, 694-701.
  • Weber, B. Stresemann, C. Brueckner, B. and Lyko, F. (2007). Methylation of human microRNA genes in normal and neoplastic cells. Cell Cycle-Landes Bioscience. 6, 1001.
  • Fabbri, M. Garzon, R. Cimmino, A. Liu, Z. Zanesi, N. Callegari, E. Liu, S. Alder, H. Costinean, S. and FernandezCymering, C. (2007). MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proceedings of the National Academy of Sciences.104, 15805-15810.
  • Kim, M.J. Yoo, S.S. Choi, Y.Y. and Park, J.Y. (2010). A functional polymorphism in the pre-microRNA196a2 and the risk of lung cancer in a Korean population. Lung Cancer. 69, 127-129.
  • Shenfield, G.M. (2004). Genetic polymorphisms, drug metabolism and drug concentrations. The Clinical BiochemistReviews/Australian Association of Clinical Biochemists.25, 203-206.
  • Vignal, A. Milan, D. SanCristobal, M. and Eggen, A. (2002). A review on SNP and other types of molecular markers and their use in animal genetics.Genetics Selection, evolution : GSE 34, 275-305.
  • Ekmekçi, A. Konaç, E. and Önen, H.İ. (2008). Gen polimorfizmi ve kansere yatkınlık. Gen. 21, 282-295.
  • http://www.ncbi.nlm.nih.gov/gene/
  • Spitz, M.R. Hong, W.K. Amos, C.I. Wu, X. Schabath, M.B. Dong, Q. Shete, S. and Etzel, C.J. (2007). A Risk Model for Prediction of Lung Cancer. Journal of the National Cancer Institute. 99, 715-726.
  • Tammemagi, C.M. Pinsky, P.F. Caporaso, N.E. Kvale, P.A. Hocking, W.G. Church, T.R. Riley, T.L. Commins, J. Oken, M.M. and Berg, C.D. (2011). Lung cancer risk prediction: prostate, lung, colorectal and ovarian cancer screening trial models and validation. Journal of The National Cancer Institute. 103, 1058-1068.
  • Karlıkaya, C. Öztuna, F. Solak, Z.A. Özkan, M. and Örsel, O. (2006). Tütün kontrolü. Toraks Dergisi. 7:51-64.
  • Frost, G. Darnton, A. and Harding, A.H. (2011). The Effect of Smoking on the Risk of Lung Cancer Mortality for Asbestos Workers in Great Britain (1971–2005). Annals of Occupational Hygiene 55, 239-247.
  • Chen, M.F. Lu, M.S. Lin, P.Y. Chen, P.T. Chen, W.C. and Lee, K.D. (2012). The role of DNA methyltransferase 3b in esophageal squamous cell carcinoma. Cancer.118, 4074-4089.
  • Shen, H. Wang, L. Spitz, M.R. Hong, W.K. Mao, L. and Wei, Q. (2002). A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Research.62, 4992-4995.
  • Liu, Z. Wang, L. Wang, L.E. Sturgis, E.M. and Wei, Q. (2008). Polymorphisms of the< i> DNMT3B</i> gene and risk of squamous cell carcinoma of the head and neck: A case–control study.Cancer Letters. 268, 158-165.
  • Sandhu, R. Rivenbark, A.G. and Coleman, W.B. (2012). Enhancement of chemo-therapeutic efficacy in hypermethylator breast cancer cells through targeted and pharmacologic inhibition of DNMT3b. Breast Cancer Research and Treatment. 131, 385-399.
  • Janssen, E.A. Slewa, A. Gudlaugsson, E. Jonsdottir, K. Skaland, I. Søiland, H. and Baak, J.P. (2010). Biologic profiling of lymph node negative breast cancers by means of microRNA expression. Modern Pathology. 23, 1567-1576.
  • Li, J. Kong, X. Zhang, J. Luo, Q. Li, X. and Fang, L. (2013). MiRNA-26b inhibits proliferation by targeting PTGS2 in breast cancer. Cancer Cell Int.13.
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Details

Primary Language Turkish
Journal Section ORİJİNAL MAKALE
Authors

Cansu OZBAYER


İrfan DEGIRMENCI This is me


Derya USTUNER This is me


Guntulu AK This is me


Faruk SAYDAM This is me


Ertugrul COLAK


Hasan GUNES This is me


Muzaffer METINTAS This is me

Publication Date July 3, 2015
Published in Issue Year 2014, Volume 36, Issue 2

Cite

Bibtex @ { otd217973, journal = {Osmangazi Tıp Dergisi}, issn = {1305-4953}, eissn = {2587-1579}, address = {}, publisher = {Eskişehir Osmangazi University}, year = {2015}, volume = {36}, pages = { - }, doi = {10.20515/otd.72122}, title = {DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi}, key = {cite}, author = {Ozbayer, Cansu and Degırmencı, İrfan and Ustuner, Derya and Ak, Guntulu and Saydam, Faruk and Colak, Ertugrul and Gunes, Hasan and Metıntas, Muzaffer} }
APA Ozbayer, C. , Degırmencı, İ. , Ustuner, D. , Ak, G. , Saydam, F. , Colak, E. , Gunes, H. & Metıntas, M. (2015). DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi . Osmangazi Tıp Dergisi , 36 (2) , . Retrieved from https://dergipark.org.tr/en/pub/otd/issue/20466/217973
MLA Ozbayer, C. , Degırmencı, İ. , Ustuner, D. , Ak, G. , Saydam, F. , Colak, E. , Gunes, H. , Metıntas, M. "DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi" . Osmangazi Tıp Dergisi 36 (2015 ): <https://dergipark.org.tr/en/pub/otd/issue/20466/217973>
Chicago Ozbayer, C. , Degırmencı, İ. , Ustuner, D. , Ak, G. , Saydam, F. , Colak, E. , Gunes, H. , Metıntas, M. "DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi". Osmangazi Tıp Dergisi 36 (2015 ):
RIS TY - JOUR T1 - DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi AU - Cansu Ozbayer , İrfan Degırmencı , Derya Ustuner , Guntulu Ak , Faruk Saydam , Ertugrul Colak , Hasan Gunes , Muzaffer Metıntas Y1 - 2015 PY - 2015 N1 - DO - T2 - Osmangazi Tıp Dergisi JF - Journal JO - JOR SP - EP - VL - 36 IS - 2 SN - 1305-4953-2587-1579 M3 - UR - Y2 - 2022 ER -
EndNote %0 Osmangazi Journal of Medicine DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi %A Cansu Ozbayer , İrfan Degırmencı , Derya Ustuner , Guntulu Ak , Faruk Saydam , Ertugrul Colak , Hasan Gunes , Muzaffer Metıntas %T DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi %D 2015 %J Osmangazi Tıp Dergisi %P 1305-4953-2587-1579 %V 36 %N 2 %R %U
ISNAD Ozbayer, Cansu , Degırmencı, İrfan , Ustuner, Derya , Ak, Guntulu , Saydam, Faruk , Colak, Ertugrul , Gunes, Hasan , Metıntas, Muzaffer . "DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi". Osmangazi Tıp Dergisi 36 / 2 (July 2015): - .
AMA Ozbayer C. , Degırmencı İ. , Ustuner D. , Ak G. , Saydam F. , Colak E. , Gunes H. , Metıntas M. DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi. Osmangazi Tıp Dergisi. 2015; 36(2): -.
Vancouver Ozbayer C. , Degırmencı İ. , Ustuner D. , Ak G. , Saydam F. , Colak E. , Gunes H. , Metıntas M. DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi. Osmangazi Tıp Dergisi. 2015; 36(2): -.
IEEE C. Ozbayer , İ. Degırmencı , D. Ustuner , G. Ak , F. Saydam , E. Colak , H. Gunes and M. Metıntas , "DNA Metiltransferaz-3b ve Metil Bağlayan Bölge Proteini-1’i Hedefleyen Mirna Gen Polimorfizmlerinin Akciğer Kanseri İle İlişkisinin Belirlenmesi", Osmangazi Tıp Dergisi, vol. 36, no. 2, Jul. 2015, doi:10.20515/otd.72122

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