Hsa-miR-3178 Targets RhoB To Mediate Drug Resistance Of Pancreatic Cancer Via The PI3K/Akt/ABC Transporters

Chemo-resistance is the main cause of poor prognosis of pancreatic cancer（PC）.Previous studies demonstrated that ATP binding cassette（ABC）transporters including P Glycoprotein（P-gp）,Breast Cancer Resistance Protein（BCRP）and Multidrug Resistance-Associated Protein 1（MRP1）proteins play important roles in drug resistance in various cancers.In recent years,microRNAs have been reported to involve in this clinical dilemma.However,whether ABC transporters and miRNAs are associated with gemcitabine resistance in pancreatic cancer remain unclear.In this study,we investigated the involvement of ABC transporters and miRNA hsa-miR-3178 in regulating gemcitabine resistance in PC.It was found that P-gp,BCRP and MRP1 were highly expressed in gemcitabine-resistant pancreatic cancer tissues and cells.Molecular docking analysis revealed that gemcitabine can bind to the ABC transporters.Hsa-miR-3178 was upregulated in gemcitabine resistance PANC-1 cells（PANC-1-GEM）as compared to its parental PANC-1 cells by real-time qPCR.Moreover,we found that hsa-miR-3178 promoted gemcitabine resistance in PC cells by CCK-8 assay,EdU assay and flow cytometric analysis.These results were verified by animal experiments.Bioinformatics analysis identified RhoB was a downstream target of hsa-miR-3178 and Western blotting and dual-luciferase reporter assay revealed that hsa-miR-3178 directly targeted RhoB.Rescue assays demonstrated that RhoB could reverse hsa-miR-3178-mediated gemcitabine resistance.Interestingly,hsamiR-3178/RhoB promoted gemcitabine resistance in PC by activating the PI3K/Akt signaling pathway and upregulating the expression of ABC transporters.Collectively,our findings suggested that hsa-miR-3178 promotes gemcitabine resistance via RhoB/PI3K/Akt signaling pathway-mediated upregulation of ABC transporters.These findings suggest that hsa-miR-3178 could be a novel therapeutic target for overcoming gemcitabine resistance in PC.