FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Pancreatic Ductal/drug therapy , DNA Damage , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Pancreatic Neoplasms/drug therapy , Carcinoma, Pancreatic Ductal/genetics , Fluorouracil/administration & dosage , Humans , Irinotecan/administration & dosage , Kaplan-Meier Estimate , Leucovorin/administration & dosage , Neoadjuvant Therapy , Outcome Assessment, Health Care/methods , Outcome Assessment, Health Care/statistics & numerical data , Oxaliplatin/administration & dosage , Pancreatic Neoplasms/genetics
Pancreatic cancer is an aggressive cancer of the digestive system, which is becoming a serious health problem worldwide. Overall survival for patients with pancreatic cancer is poor, mainly due to a lack of biomarkers to enable early diagnosis and a lack of prognostic markers that can inform decision-making, facilitating personalized treatment and an optimal clinical outcome. ncRNAs play an important role in pancreatic carcinogenesis. Here we review the literature on the role of ncRNAs as biomarkers in pancreatic cancer. We focus on the significance of ncRNAs as markers for early diagnosis, as prognostic biomarkers able to inform clinical management and as targets for novel therapeutics for patients with pancreatic cancer.
Biomarkers, Tumor , Gene Expression Regulation, Neoplastic , Pancreatic Neoplasms/genetics , RNA, Untranslated , Adenocarcinoma/genetics , Genetic Therapy , Humans , MicroRNAs/genetics , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/therapy , Prognosis , RNA, Long Noncoding , RNA, Messenger
