TGF-βRII knock-down promotes tumor growth and chemoresistance to gemcitabine of pancreatic cancer cells via phosphorylation of STAT3
Résumé
Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the western countries because of a lack of early diagnostic markers and efficient therapeutics. At the time of diagnosis, more than 80% of patients have metastasis or locally advanced cancer and are therefore not eligible for surgical resection. Pancreatic cancer cell also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatment for PDAC.
TGF-β possesses both tumor-suppressive and oncogenic activities in pancreatic cancer. TGF-β signalling pathway plays complex role during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as tumor suppressor pathway. TGF-β binds to its receptor TGF-βRII and activates different pathways: canonical pathway involving the Smad proteins and alternative pathways such as MAPKs. Smad4 is mutated in 50-80% of PDAC. Mutations of TGF-βRII also occurs (5-10%). In order to decipher the role of TGF-β in carcinogenesis and chemoresistance, we decided to characterize the knocking down of TGF-βRII that is the first actor of TGF-β signalling. We developed pancreatic cancer cell lines stably invalidated for TGF-βRII and studied the impact on biological properties of pancreatic cancer cells both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to. TGF-βRII silencing also leads to S727 STAT3 and S-63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype.
In the future, the better understanding TGF-β signaling pathways and underlying cellular mechanisms in chemoresistance to gemcitabine may bring new therapeutic tools to clinicians.
Domaines
CancerOrigine | Fichiers produits par l'(les) auteur(s) |
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