Upregulation Of MiR-374b-5p Ameliorates Chemotherapeutic Resistance Of Pancreatic Cancervia The Direct Targeting Of Several Anti-apoptoticproteins

Background:Pancreatic cancer is one of the most devastating malignancies of the gastrointestinal tract as well as one of the most common causes of cancer-associated mortality worldwide.Surgery is the optimal method of treating patients with pancreatic cancer,however,the application of surgical therapy in patients with pancreatic cancer is limited,as the majority of patients are at an advanced stage of the disease at diagnosis.Indeed,?20% of patients with pancreatic cancer are suitable to undergo such surgery.For the majority of patients with pancreatic cancer,the primary method of treatment is chemotherapy,and gemcitabine is the most common chemotherapeutic drug used to treat patients with inoperable pancreatic cancer.Although progress has been made in the treatment of pancreatic cancer over the past few decades,the median survival time of such patients remains <1 year.The failure of chemotherapy is attributed to the complete resistance against chemotherapeutic drugs and chemotherapy resistance presents a major clinical challenge in the treatment of cancer.Therefore,it is important to understand the molecular mechanisms underlying the development of chemoresistance in pancreatic cancer in order to develop effective therapeutic targets.The resistance of cancer cells to a wide spectrum ofchemotherapeutic drugs may be associated with the intrinsic resistance of cancer cells and/or acquired resistance followingseveral cycles of chemotherapy.The most common mechanismby which chemoresistance arises is the development ofefflux pumps on the surface of tumor cells that eject anticancerdrugs from inside tumor cells to the outside environment.Other mechanisms include dna repair,apoptosis,tumor microenvironment,drug metabolism and angiogenesis,all of which serve acrucial role in the development of drug resistance of cancercells.Therefore,it is crucial to develop comprehensiveunderstanding of the specific mechanism by which chemoresistancearises in pancreatic cancer cells in order to identifya novel therapeuticstrategy to overcome chemoresistanceand improve the clinical therapeutic response of patients withpancreatic cancer.MicroRNA(miRNA)post-transcriptionally regulate a varietyof target genes by binding to the 3'-untranslated region(3'-UTR)of their target genes.The aberrant expression ofmiRNAs serves either oncogenic or tumor-suppressive rolesin the tumorigenesis,progression and metastasis of varioustypes of cancer.Previous studies have demonstratedthat miRNAs are important mediators of chemoresistancein pancreatic cancer.Chaudhary et al reported thatmiR? 205-5p was differentially downregulated in pancreaticcancer cells and tissues.It was also demonstrated thatthe ectopic expression of miR-205-3p in combination withgemcitabine significantly reduced the proliferation and tumorgrowth of pancreatic cancer cells in mouse models.Furthermore,the oncogenic miRNA miR-181 c is dramaticallyelevated in pancreatic cancer tissues and this high expressionof miR-181 c induces chemoresistance in pancreatic cancer byinactivating the Hippo signaling pathway.These resultsindicate that the dysregulation of miRNAs serves an importantrole in the development of chemoresistance in pancreaticcancer.The purpose of this study was to explore the mechanism by which miRNAs are involved in chemoresistance in pancreatic cancer.Previous bioinformatics analysis has found that miR-374b-5p expression is decreased in patients with pancreatic cancer,and miR-374b-5p expression is lower in chemotherapy-resistant patients;and miR-374b-5p directly targets the 3'-UTR region ofseveral anti-apoptotic proteins.however,how miR-374b-5p involved in chemoresistance in pancreatic cancer is unknown and whether it is mediated by several anti-apoptotic proteins remains to be elucidated.Materials and Methods:The present study measured miR-374b-5p expression byreverse transcriptionquantitative polymerase chain reaction(RT-qPCR)and evaluated whether there was an association between miR-374b-5p levels,clinicopathological characteristicsand overall and progression-free survival of patients withpancreatic cancer.The effects of miR-374b-5p expressionon chemoresistance were examined by performing gain orloss of function assays in vitro and in vivo and the potentialtargets of miR-374b-5p were identified using bioinformaticsanalysis,RT-qPCR,western blotting,luciferase reporterand RNA immunoprecipitation assays.Furthermore,the study observedwhether the resistance to gemcitabine in pancreatic cancer whichcausedbyanti-miR-374b-5p wasmediatedby BCL2,BIRC3 and XIAP.Results:The present study shows that miR-374b-5p expression was decreased in pancreaticcancer tissues,particularly in chemoresistant pancreaticcancer tissues,and the low expression of miR-374b-5p wasstrongly associated with chemotherapeutic resistance,aswell as poor overall and progression-free survival in patientswith pancreatic cancer.The upregulation of miR-374b-5pdecreased,whereas miR-374b-5p silencing increased,thechemoresistance of pancreatic cancer cells to gemcitabinein vitro and in vivo.Furthermore,the results of the currentstudy revealed that miR-374b-5p targeted several anti-apoptoticproteins,including BCL2,BIRC3 and XIAP.The resistance to gemcitabine in pancreatic cancer whichcausedbyanti-miR-374b-5p wasmediatedby BCL2,BIRC3 and XIAP.Conclusion:The results revealedthat the upregulation of miR-374b-5p ameliorated chemotherapeutic resistance of pancreatic cancer via the direct targeting of several anti-apoptotic proteins,including BCL2,BIRC3 and XIAP.