Soutenance de thèse : YB-1 as a Cancer Biomarker and its Expression Correlation with Base Excision Repair Factors and with Cisplatin Resistance

Par Ahmad Hamoud (IBS/Groupe Imagerie Intégrée de la Réponse au Stress)

Cancer is a complex disease characterized by the uncontrolled growth of cells, which is often fatal if not managed effectively. The identification and characterization of biomarkers are crucial for the efficient diagnosis and prognosis of cancer. Among these, the Y-box binding protein 1 (YB-1) has emerged as a promising candidate. YB-1 functions as a proto-oncogene and is implicated in many hallmarks of cancers. High YB-1 expression and nuclear localization have been associated with poor prognosis and chemoresistance in several tumor types. Interestingly, YB-1 stimulates the DNA repair activity of the DNA glycosylase NTH1, an enzyme involved in the Base Excision Repair (BER) pathway. In vivo, human breast cancer MCF7 cells were partially resensitized to the chemotherapeutic agent cisplatin by inhibiting the YB-1/NTH1 interaction.

The first objective of my thesis was to evaluate YB-1 mRNA levels as a potential pan-cancer biomarker through bioinformatics analyses of publicly available data from cancer patients, healthy tissues, and cancer cell lines. We also extended our study to BER factors to evaluate their potential as reliable prognostic or diagnostic biomarkers, either individually or in combination with YB-1. This approach generated a comprehensive atlas of the transcript levels of YB-1, NTH1 and other BER gene expression profiles, revealing significant overexpression of YB-1 in most tumor types and cancerous cell lines. Furthermore, our analyses demonstrated the potential of YB-1 mRNA as an early diagnostic and a prognostic biomarker in several cancers. In parallel, we observed consistent overexpression of BER factors, including APE1 and PARP1, in tumor samples compared to healthy tissues, with moderate to strong positive correlations between their expression and that of YB-1.

The second objective of my PhD was to experimentally investigate the relationship between YB-1, NTH1 and cisplatin resistance by quantifying their expression at both the mRNA and protein levels across a selected panel of cell lines. Unexpectedly, we found that lower YB-1 expression correlates with higher cisplatin resistance, and YB-1 knockdown in PANC1 cells further increased cisplatin resistance. Based on the recent literature, we propose a model to explain these findings. In contrast, NTH1 expression levels showed a positive correlation with cisplatin resistance, consistent with previous reports.

Altogether, this work underscores the multifaceted role of YB-1 in cancer biology and its intricate relationship with DNA repair pathways. It highlights YB-1 mRNA as a promising biomarker for cancer diagnosis and prognosis, while also revealing unexpected aspects of its involvement in chemoresistance. These findings open new perspectives for developing novel therapeutic strategies targeting YB-1 and BER components to overcome drug resistance in cancer.