Rahim Ağzı Kanser Alt-Tiplerine Özgü Moleküler Hedef, Biyoişaretçi Adaylar ve Yeniden Konumlandırılan İlaçların Belirlenmesi

Yıl 2021, , 537 - 548, 30.12.2021

Beste Turanlı

https://doi.org/10.7240/jeps.869943

Öz

Hassas tıp uygulamaları, geleneksel tedaviden farklı olarak kanser hastaları arasındaki bireysel farklılıkları dikkate alarak hastaları sınıflandırır. Yapılan alt tipleme ile kanser teşhisi ve tedavi yanıtının tahmini için yeni biyobelirteçlerin belirlenmesi gerekmektedir. Bu çalışmada, sistem biyolojisi yaklaşımları kullanılarak, rahim ağzı kanserinin en yaygın onkojenik iki türü olan HPV-16 enfekte ve HPV-18 enfekte grupları ayrı ayrı incelenmiştir. Her iki alt-tip için kanserin gelişimi ile ilgili ayırıcı biyobelirteçler sunularak, hassas tıp uygulaması olabilecek alt-tip spesifik teşhis ve tedavi yöntemleri sunma konusunda moleküler hedefler sunulması amaçlanmıştır. Literatürde var olan çalışmalar, hastalık heterojenliği ve alt-tip bilgilerinden bağımsız olarak doğrudan rahim ağzı kanserine odaklanmıştır. İlk defa bu çalışmada HPV-16 ve HPV-18 enfekte hasta grupları ile ilgili transkriptomik veri ayrı ayrı çalışılmıştır. Rahim ağzı kanserinde alt-tip spesifik diyagnostik, prognostik ve ilaç hedefi olabilecek biyobelirteçlerini belirlemek için mikrodizi meta-analizi yapılmıştır. İlk olarak incelenen protein-protein etkileşimlerindeki hub proteinlerde iki alt-tipte de ortak olan 8 protein (AR, AURKA, BRCA1, CDKN2A, EZH2, MYC, PCNA, STAT) dışında, 17’şer protein alt-tiplere spesifik hub proteinler olarak bulunmuştur. Transkripsiyonel düzenlemede önem arz eden TF ve miRNA’lar arasında işaretçi molekül algoritması ile ön plana çıkanlar bulunmuştur. TF’lerde alt-tipleri ayırt edebilecek belirgin farklılık gözlenmemekle birlikte, sadece HIF1α HPV-18 enfekte grubunda işaretçi TF bulunmuştur. HPV-16 spesifik sadece hsa-miR-101-3p ve hsa-let-7d-5p bulunmuştur. HPV-18 enfekte gruba spesifik ise 81 miRNA vardır. Çalışmanın en sonunda ise hub proteinlerin bazılarını hedef alan ilaçlar üzerinden ilaç yeniden konumlandırma yapılmıştır. HPV-16 enfekte kanser tedavisi için ibuprofen ve procainamide ilaçları; HPV-18 enfekte kanserler için ise hydralazine ve memantin önerilen ilaçlardandır.

Anahtar Kelimeler

Sistem biyotıbbı, rahim-ağzı kanseri, biyobelirteçler, hastalık alt-tipleri, ilaç yeniden konumlandırma

Destekleyen Kurum

TÜBİTAK

Proje Numarası

119S999

Teşekkür

Bu çalışma, 119S999 numaralı TÜBİTAK 1002 Araştırma projesi kapsamında desteklenmiştir.

Kaynakça

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