Abstract
Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in the Western world 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 cells also harbour a high resistance to chemotherapeutic drugs such as gemcitabine that is one of the main palliative treatments for PDAC. Proteins involved in TGF-β signaling pathway (SMAD4 or TGF-βRII) are frequently mutated in PDAC (50–80%). TGF-β signalling pathway plays antagonistic roles during carcinogenesis by initially inhibiting epithelial growth and later promoting the progression of advanced tumors and thus emerged as both tumor suppressor and oncogenic pathways. In order to decipher the role of TGF-β in pancreatic carcinogenesis and chemoresistance, we generated CAPAN-1 and CAPAN-2 cell lines knocked down for TGF-βRII (first actor of TGF-β signaling). The impact on biological properties of these TGF-βRII-KD cells was studied both in vitro and in vivo. We show that TGF-βRII silencing alters tumor growth and migration as well as resistance to gemcitabine. TGF-βRII silencing also leads to S727 STAT3 and S63 c-Jun phosphorylation, decrease of MRP3 and increase of MRP4 ABC transporter expression and induction of a partial EMT phenotype. These markers associated with TGF-β signaling pathways may thus appear as potent therapeutic tools to better treat/manage pancreatic cancer.
Highlights
Pancreatic cancers (PC) are projected to become the second leading cause of cancer-related deaths by 2030 [1]
Expression of TGF-βRI, TGF-βRII, TGF-βRIII, Smad2, Smad3, and Smad7 was confirmed by RT-PCR in CAPAN-1 and CAPAN-2 cells
Four different shRNA sequences were used to establish four different cell lines designated as TGF-βRIIKD6, TGF-βRIIKD7, TGF-βRIIKD8 and TGF-βRIIKD9
Summary
Pancreatic cancers (PC) are projected to become the second leading cause of cancer-related deaths by 2030 [1]. The survival curve is extremely short (6 months) and the survival rate at 5 years is very low (3%). This dramatic outcome is related to a lack of therapeutic tools and early diagnostic markers which makes pancreatic cancer the most deadly cancer. At the time of diagnosis, more than 80% of PC are already metastatic or locally advanced and only about 10% to 15% of patients are considered. Remaining patients that do not benefit from surgery will receive palliative chemotherapy and notably gemcitabine, a fluorinated analog of deoxycytidine that is a major chemotherapeutic drug used in firstline in advanced PC. Deciphering mechanisms responsible for PC cell resistance to gemcitabine is crucial to improve efficacy of the drug and propose more efficient therapies
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