Low-intensity Ultrasound Enhanced The Antitumor Effects Of Cisplatin In Non-small Cell Lung Cancer Cells Via Inhibiting MiR-124/STAT3 Signaling

Objective: To investigate the effect of low-intensity ultrasound(US)on cisplatin(CDDP)in the treatment of non-small cell lung cancer cell(NSCLC)and its related mechanisms,so as to provide evidence for the application of low-intensity ultrasound in non-small cell lung cancer.Methods: 1.A549 cells were divided into 4 groups: control group,cisplatin group,low-intensity ultrasound group and low intensity ultrasound combined with cisplatin group.First,the effects of low-intensity US on cisplatin mediated cell viability,induction of apoptosis and reactive oxygen species(ROS)production were determined by CCK-8 assay,flow cytometry analysis and fluorescent probe(DCFH-DA),respectively.2.To profile the expression of microRNAs that are involved in the combined effects of cisplatin and low-intensity US,microRNA microarray was applied and the significant high expressed microRNA was selected for follow-up study.3.Loss-of-function study was performed to determine the role of the high expressed microRNA in the combined effect of cisplatin and low-intensity US exposure.4.We predicted the candidate target genes for the high expressed microRNA through bioinformatics.A luciferase reporter assay was performed to validate the interaction between the high expressed microRNA and target gene followed by qRT-PCR confirmation.5.Afterward,After inhibiting the expression of the high expressed microRNA,the possible mechanism was explored by detecting expression level of the target gene and its downstream gene.Results: 1.Compared with other groups,low-intensity ultrasound combined with cisplatin could significantly decrease cell viability(P<0.05)and induce cell apoptosis(P<0.05)and ROS production(P<0.05).2.Compared with the cisplatin group,the expression level of miR-124 was significantly higher in the low intensity ultrasound combined with cisplatin group(P<0.01).3.After inhibition of ROS,the miR-124 expression level in low-intensity ultrasound combined with cisplatin group was significantly decreased(P<0.01).After inhibiting the expression of miR-124,the antitumor effect of low intensity ultrasound combined with cisplatin on A549 cells was reduced.4.MiR-124 suppressed STAT3 expression by directly targeting its 3?-UTR.5.After inhibiting the expression of miR-124,the expression level of STAT3,p-STAT3,Bcl-2 and Bcl-xL increased significantly(P<0.05).Conclusion: 1.Low intensity ultrasound and cisplatin played an anti-tumor effect by reducing the cell viability,inducing apoptosis and producing ROS in A549 cells.2.There was a synergistic effect of low intensity ultrasound combined with cisplatin on the antitumor effect of A549 cells.3.Low intensity ultrasound exerts the anti-tumor effect of cisplatin through miR-124/STAT3 signaling pathway.