Investigation of the Relationship of Human Endogenous Retroviruses with Cancer

Abstract

Transposons are mobile elements of DNA that have the ability to change their locations in the genome. Transposons perform the displacement process in the genome by a mechanism called transposition and are divided into two subclasses as DNA and RNA transposons according to their transposition mechanism. RNA transposons, also called retrotransposons including endogenous retroviruses (ERVs) that play an important role in human evolution. Human endogenous retroviruses (HERV), which make up about 8% of the human genome, are grouped under 3 classes. Human endogenous retrovirus K (HERV-K), which is in the second class, is the most active HERV in the human genome considered to integrate to human genome in a close time. According to the gene expression analysis of HERV-K, it exhibited that HERV-K plays a role in the emergence of various cancer types such as ovarian, breast and skin cancer. The relationship of HERVs to cancer development has been investigated for a long time. Although HERV proteins have been detected in cancer cells, the role of HERVs in cancer development has not been clearly understood. Recent studies revealed that HERV proteins, are at high levels in cancer cells, can be used as the main target for the immune response involved in cancer therapy. New approaches, which combine histone deacetylase inhibitors and checkpoint inhibitors, are also being tested for use in cancer therapy. HERV expression initiates the immune system response by activating the pattern recognition receptors of single-stranded RNA in the cytosol, which activates the interferon type 1 response. As a result, it is predicted that cancer development can be prevented by increasing the recognition of cancer cells by CD8 T cells. This new approach consisting of a combination of histone deacetylase and checkpoint inhibitors, will increase its anti-tumor activity and will provide new hope in cancer therapy.

Keywords

• Transposon
• Human endogenous retroviruses
• Cancer

Project Number

1919B011900082

İnsan Endojen Retrovirüslerin Kanserle Olan İlişkisinin İncelenmesi

Abstract

Transpozonlar, genomdaki yerlerini değiştirebilme özelliğine sahip olan hareketli DNA parçalarıdır. Transpozonlar genomdaki yer değiştirme işlemini, transpozisyon olarak adlandırılan bir mekanizma ile gerçekleştirmekte ve sahip oldukları transpozisyon mekanizmasına göre DNA ve RNA transpozonları olarak iki alt sınıfa ayrılmaktadırlar. Retrotranspozonlar olarak da adlandırılan RNA transpozonları, insanın evrim sürecinde önemli rol alan endojen retrovirüsleri (ERV) içermektedir. İnsan genomunun yaklaşık %8’ini oluşturan insan endojen retrovirüsleri (HERV) 3 sınıf altında toplanmakta olup ikinci sınıfta yer alan insan endojen retrovirüs K (HERV-K), insan genomuna yakın sayılabilecek bir zamanda entegre olan, insan genomundaki en aktif HERV’dir. HERV-K’nın gen anlatım analizleri incelendiğinde, ovaryum, meme ve deri kanseri gibi çeşitli kanser türlerinin ortaya çıkmasında HERV-K’nın rol aldığı görülmektedir. HERV’lerin kanser gelişimi ile olan ilişkisi uzun süredir araştırılmaktadır. Kanser hücrelerinde HERV proteinleri saptanmış olsa da HERV’lerin kanser gelişimindeki rolü kesin olarak anlaşılamamıştır. Son dönemde yapılan çalışmalar kanser hücrelerinde yüksek seviyede anlatım yaptığı gösterilen HERV proteinlerinin, kanser tedavisinde rol alan immün yanıt için ana hedef olarak kullanılabileceğini ortaya koymaktadır. Histon deasetilaz inhibitörleri ve kontrol noktası inhibitörlerinin kombinasyonundan oluşan yeni yaklaşımlar da kanser tedavisinde kullanılmak üzere test edilmektedir. HERV anlatımı, interferon tip 1 yanıtını etkinleştiren, sitozoldeki tek iplikli RNA’nın kalıp tanıma reseptörlerini aktive ederek immün sistem yanıtını başlatmaktadır. Bunun sonucunda CD8 T hücreleri tarafından gerçekleştirilen kanser hücresi tanınması arttırılarak kanser gelişiminin engellenebileceği öngörülmektedir. Histon deasetilaz ve kontrol noktası inhibitörlerinin kombinasyonundan meydana gelen bu yeni yaklaşım, anti-tümör aktivitesini arttırarak kanser tedavisinde yeni bir umut oluşmasına olanak sağlayacaktır.

Keywords

• Transposon
• İnsan Endojen Retrovirüsleri
• Kanser

Supporting Institution

TÜBİTAK

Project Number

1919B011900082

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