TGF-βRII knock-down promotes tumor growth and chemoresistance to gemcitabine of pancreatic cancer cells via phosphorylation of STAT3

Drubay, V.; Skrypek, N.; Cordiez, L.; Vasseur, R.; Schulz, C.; Boukrout, N.; Duchene, B.; Coppin, L.; Van Seuningen, I.; Jonckheere, N.

doi:10.1101/352963

bioRxiv · 10.1101/352963

TGF-βRII knock-down promotes tumor growth and chemoresistance to gemcitabine of pancreatic cancer cells via phosphorylation of STAT3

Drubay, V.·Skrypek, N.·Cordiez, L.·Vasseur, R.·Schulz, C.·Boukrout, N.·Duchene, B.·Coppin, L.·Van Seuningen, I.·Jonckheere, N.

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Abstract

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.\n\nTGF-{beta} possesses both tumor-suppressive and oncogenic activities in pancreatic cancer. TGF-{beta} 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-{beta} binds to its receptor TGF-{beta}RII 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-{beta}RII also occurs (5-10%). In order to decipher the role of TGF-{beta} in carcinogenesis and chemoresistance, we decided to characterize the knocking down of TGF-{beta}RII that is the first actor of TGF-{beta} signalling. We developed pancreatic cancer cell lines stably invalidated for TGF-{beta}RII and studied the impact on biological properties of pancreatic cancer cells both in vitro and in vivo. We show that TGF-{beta}RII silencing alters tumor growth and migration as well as resistance to. TGF-{beta}RII 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.\n\nIn the future, the better understanding TGF-{beta} signaling pathways and underlying cellular mechanisms in chemoresistance to gemcitabine may bring new therapeutic tools to clinicians.

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Drubay, V., Skrypek, N., Cordiez, L., Vasseur, R., Schulz, C., Boukrout, N., Duchene, B., Coppin, L., Van Seuningen, I., Jonckheere, N.. 2018-06-21. TGF-βRII knock-down promotes tumor growth and chemoresistance to gemcitabine of pancreatic cancer cells via phosphorylation of STAT3. https://doi.org/10.1101/352963

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