INFORMAZIONI SU
SIRCH Deborah
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Supervisore:Prof. Tell Investigating the structural and functional roles of onco-miRNA containing G4-structures and the role of APE1 in their regulation for the identification of new anti-cancer drugs in ovarian cancer therapy |
| Ovarian cancer (OC) is the most common and lethal gynecological tumor in women worldwide. High-grade serous ovarian cancer (HGSOC) is one of the most frequently and aggressive histological subtype of epithelial ovarian cancer, usually associated with a poor prognosis. Nowadays, despite advances in OC clinical management, novel and personalized therapeutic strategies are highly required. Recent findings regarding tumoral progression and chemoresistance in OC rely on epitranscriptional mechanisms involving the dysregulation of oncogenic miRNA (oncomiR) biogenesis. High exposition to oxidative stress, induces modifications of guanines (G) in the seed regions of miR. Damaged miR, including abasic (AP) and oxidized (8-oxoG), may have detrimental effects on gene expression promoting cancer progression. Recently, an alternative pathway of miR maturation, specifically tuned to G-rich pre-miRs, which involves a non-canonical secondary structure called RNA G-quadruplex (rG4), has been described. In this context, Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is an essential enzyme of the BER pathway which is considered a prognostic and predictive factor in OC cancers. APE1 is already known to be involved in the oncomiRNA maturation and recently it has been identified a miR-signature regulated by APE1 characterized by the presence of rG4 structures. From these findings, which suggest unexplored APE1 mechanisms, this project will investigate the role of APE1 in rG4-miRs biogenesis, which may explain its role in chemoresistance mechanisms in OC models. Specifically, we will: i) identify and characterize predictive rG4-oncomiR regulated by APE1 in OC and ii) define the effects of AP-sites and 8-oxoG in the previously selected rG4-oncomiRs. The ultimate goal of the project will be focused on the development of novel specific anti-cancer strategies based on the identification of small molecules able to specifically inhibit the interaction between APE1 and rG4-miR. In this context, we will explore novel strategies to target the non-canonical APE1-rG4-onco-miR axis, which is relevant for cancer resistance. | |