Abstract
Abstract Introduction: Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers in western countries with an extremely poor prognosis because of a lack of efficient therapeutic tools. Gemcitabine, a fluorinated analog of deoxycytidine, is the main chemotherapy in PDAC, but survival remains poor. FOLFIRINOX, a more aggressive protocol combining 5-fluorouracil (5-FU), irinotecan/SN-38, oxaliplatin and leucovorin, emerged as a new option in patients with metastatic pancreatic cancer. MUC4 is a membrane-bound oncomucin involved in pancreatic cancer (PC) pathogenesis and chemoresistance to gemcitabine. MUC4 is not expressed in healthy pancreas whereas its expression increases constantly during carcinogenetic progression. In this work, we aimed to decipher the involvement of MUC4 and associated cellular mechanisms in chemoresistance to FOLFIRINOX drugs. Material and Methods: MUC4 expression was knocked down (KD) by stable ShRNA in CAPAN-1/-2 PC cells. IC50 and cell viability to FOLFIRINOX drugs were determined by tetrazolium salt (MTT) assays. Expression of genes involved in drug metabolism was assessed by quantitative RT-PCR (qRT-PCR) and Western blot. MiRnomes of Mock and MUC4-KD cells were determined using miRNA array (8x15K Agilent). Results: MUC4 depletion in PC cells leads to an increase of sensitivity to 5-FU and to an increased resistance to oxaliplatin. Combined treatments of 5-FU and oxaliplatin (FOX) lead to an intermediate survival rate suggesting additional effects. This altered chemosensitivity is associated with an altered expression of drug transporters/channels and drug metabolism actors. Notably, an increase of CTR1 and ATP7B transporters and DPYD enzyme was observed in MUC4-KD cells. Furthermore, we have observed downregulation of miR-96-5p, miR-132-3p and miR-210 suggesting a possible link between MUC4 expression, drug resistance and regulation by miRNAs. The involvement of these molecules is currently validated by transient RNA interference and miRNA transfections. Conclusion: this work led to the identification of proteins and miRNAs specifically involved in priming PC chemoresistance. These factors may represent critical therapeutic targets and also robust prognostic/predictive markers, and thus provide better healthcare and management of PC patients. Citation Format: Nicolas Skrypek, Nihad Boukrout, Fatima Lahdaoui, Céline Schulz, Romain Vasseur, Belinda Duchêne, Isabelle Van Seuningen, Nicolas Jonckheere.{Authors}. The MUC4 oncomucin mediates resistance of human pancreatic cancer cells to FOLFIRINOX drugs. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B31.
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