Isolation of a new oncogene in pancreatic cancer

The pancreatic ductal adenocarcinoma is already known as being a poor prognostic disease. The only curative treatment is the surgical resection which is only accessible for 15% of the patients and with a bad 5-years survival rate. This tumor entity is associated with a high degree of drug resistance. These facts show the importance to find new therapeutic targets. PTF1-P48 is well known as being a transcription factor during pancreatic differentiation, maintain of acinar phenotype and as playing an antiproliferative role. Therefore, the loss of expression of P48 could play an important role during pancreatic oncogenesis.We identified the protein TRIP12 as being a new partner of P48. TRIP12 belong to the family of the E3 ubiquitin ligase, the role of this family of protein is to target different proteins to induce their degradations by the proteasome. The preliminary works of the team have already demonstrated an interaction of the two proteins in vitro, and that P48 is degraded by the proteasome.The purpose of this work was to show the action of TRIP12 on the degradation of P48, its effect on the proliferation of tumoral cells, and to characterize its expression in pancreatic pre-neoplastic tissues.To achieve this goal, I have confirmed the antiproliferative effect of P48 with a first cell model. Then I tried to create a second cell model overexpressing P48 and TRIP12 jointly to properly highlight their interaction. Then I characterized the expression of TRIP12 in various cell lines used in pancreatic cancer research. And finally I highlighted with a histological analysis the early expression of TRIP12 during pancreatic carcinogenesis.To conclude, TRIP12 seems to play a pro-oncogenic role by its interaction with P48 anti-oncogenic factor, it could be a new therapeutic target or diagnostic marker. However, in order to claim this role, we must continue the work to show this role in vitro with a new cellular model then in-vivo.