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

Yıl 2014, Cilt: 36 Sayı: 2, - , 03.07.2015

Cansu Ozbayer İrfan Degırmencı Derya Ustuner Guntulu Ak Faruk Saydam Ertugrul Colak Hasan Gunes Muzaffer Metıntas

Öz

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.

 

Anahtar Kelimeler

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