Implication de la voie alternative NF-kappa B dans le cancer de la prostate

Prostate cancer (PCa) is the most frequently diagnosed cancer and represents the third cause of cancer-death in Canadian men. Despite effective first-line therapies, many patients experience disease recurrence where PCa progresses toward a more aggressive form. Several parameters, largely clinical, have been used to predict the progression of PCa but their accuracy is still limited and implies the need for new biomarkers to fill this gap. Previous research from the laboratory has demonstrated that the transcription factor NF-B, and its nuclear localization, could be such a prognostic biomarker. Studies in our laboratory and elsewhere have correlated RelA(p65) with a clinical progression in PCa, underlining the importance of the classical NF-B pathway. The involvement of the alternative NF-B pathway in the progression of PCa was also suggested in one of our studies showing the correlation between the nuclear distribution of RelB and Gleason score. While the classical pathway is well documented and its involvement in the PCa progression established, the alternative NF-B pathway remains largely unexplored. This thesis describes two research objectives that aims to clarify the involvement of the alternative NF-B pathway in PCa. The first objective assessed the impact of the alternative NF-B pathway activation on the biology of PCa cells. RelB overexpression in 22RV1 PCa cells highlighted an effect of the alternative NF-B pathway on cell proliferation and autophagy. Its dual role in cell growth and a form of cell death requires further study to understand the balance of these in PCa tumorigenesis. To date no study has addressed the comparative prognostic potential of both the classical and alternative NF-B pathways simultaneously. Therefore the second objective of this research project was to analyze both RelA(p65) and RelB at a cellular level in the same tissue of patients with PCa to determine their unique and combined contribution to predicting biochemical recurrence in patients. This analysis was possible through immunofluorescent labeling of RelA (p65) and RelB, and was followed by a quantitative and objective analysis using an appropriate software. Our work confirmed the predictive value of RelA(p65) for biochemical recurrance. Combining RelA(p65) with RelB weakened the association, and  RelB on its own was not found to predict biochemical recurrance. Ultimately, the research presented here has clarified the involvement of the alternative NF-B pathway on the biology of PCa. Its impact on the growth of PCa cells as well as autophagy reveals the dual role of the alternative NF-B pathway in PCa tumorigenesis. This exhaustive study of NF-B in PCa tissues further underscores the importance of the classical pathway whose clinical interest is mainly associated with RelA(p65) status. Thus, although RelB shows no potential as a clinically exploitable biomarker, further studies are needed to determine whether RelB contributes, either positively or negatively, and in a temporal fashion, to PCa progression.

Keyphrases: NF-kappaB, RelB, RelA(p65), immunofluorescence, prostate cancer, autophagy, immunofluorescence