Cellular senescence was originally described as the cell cycle arrest that accompanies the exhaustion of replicative potential in cultured primary mammalian cells. Whereas ‘replicative’ senescence is triggered by telomere erosion, other stimuli such as activated oncogenes, oxidative stress, DNA damage and sub-optimal culture conditions can also induce a senescent phenotype called ‘premature’ senescence or ‘stasis’. Senescence acts as a potent antitumor mechanism. Malignant transformation occurs after the bypass of senescence caused by mutations in oncogenes and tumour suppressors. Thus, novel genes linked with oncogenesis can be isolated by identifying genes regulating senescence. As the majority of solid tumours arise from cells of epithelial origin, the aim of the current project is to identify genes controlling senescence in epithelial cells. Specifically, human prostate epithelial cells (HprECs) will be studied as the corresponding prostate cancer represents the most frequent cancer amongst men. A genetic screening for senescence bypass will be performed in these cells using a retroviral shRNA library. The validated genes will be prioritized thanks to a parallel microarray based-analysis of transcriptional changes associated with senescence in HPrECs and to existing databases that evaluate expression profiles in human tumours. The expression of the relevant candidates will be then confirmed in a wider and independent subset of clinical tumour samples using tissue micro-array. Finally, the oncogenic properties of the candidate genes will be analysed in several models of tumourigenesis. Overall, the investigation described here aims at using senescence as a system to identify novel tumour suppressor genes.
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