Adenovirus mediated RNA interference as new therapeutic tool against cervical cancer
Cervical cancer is the third most common female cancer. Infection by human papillomavirus (mainly HPV-16 and 18), with tropisms for mucosal or cutaneous squamous surfaces, is the major etiological agent implicated in cancer and tumor development. After infection, the oncogenic process is triggered by integration of oncoproteins E6 and E7 coding regions into the host cell genome. After integration, these oncoproteins interfere with the cell cycle and induce immortalization and cellular transformation of normal cells. The best known function of these two oncoproteins is the degradation of tumors suppressors p53 and pRb respectively. My thesis project consisted in the development of adenoviral vectors expressing miRNA directed against E6 oncoprotein. Their in vitro expression resulted in cellular death by apoptosis of the treated tumor cells, and allowed reduction of tumor growth in vivo in nude mice xenografts. In addition, the adenoviral therapeutical strategy showed its possible extensions on other types of HPV-positive cancers, but also through the possible expression of different therapeutic molecules aimed at preventing the interaction of viral oncoproteins, such as E6, with their cellular partners. These abolished interactions prevent oncoproteins from exercising their biological activities implicated in the development of cancers. In conclusion, we can say that adenoviruses can also be seen as functional tools suppressing E6 and enabling to highlight the repercussions of its suppression on other cellular processes.