Effect of Yifei Sanjie Pills(益肺散结丸)Combined with Cisplatin on Plasma Exosomal miRNAs in Lewis Lung Cancer Tumor-derived Mice
Objective To investigate the tumor inhibition effect and mechanism of Yifei Sanjie Pills(益肺散结丸,YSP)on lung cancer.Methods Lewis lung cancer tumor-derived mice were established and divided into four groups including model control group,cisplatin group,cisplatin+YSP low-dose group and cisplatin+YSP high-dose group,with 12 mice in each group.The corresponding interventions were given for 14 days.The tumor volume was measured on the 0th,3rd,7th,10th and 14th days of administration to evaluate the tumor growth.The plasma and tumor tissue were collected on the 15th day.Plasma from the model group,the cisplatin group and the cisplatin+YSP high-dose group were selected,and plasma exosomes were extracted;the differences in miRNA expression among the groups were detected and analyzed by second-generation sequencing technology,and the potential mechanism of action of YSP was investigated by principal component analysis,biofunctional enrichment analysis and miRNA-target gene regulatory network analysis.Quantitative real-time PCR was used to detect the expression of miRNA-615-3p in tumor tissues,and the relationship between miRNA-615-3p and overall survival of lung cancer were analyzed using the Kaplan-Meier plotter(kmplot.com)database.Results Compared to that of the model control group,the tumor volume of the cisplatin group on day 10,and the cisplatin+YSP low-and high-dose groups on day 7,10,and 14 were significantly reduced(P＜0.05 or P＜0.01).Compared to that of the cisplatin group,the tumor volume of the cisplatin+YSP low-and high-dose groups on day 10 and 14 was significantly reduced(P＜0.05).The principal com-ponent analysis of miRNA expression profiles showed significant differences in miRNA expression between different intervention groups.There were 21 differentially expressed miRNAs between the model control group and the cisplatin group,50 differentially expressed miRNAs between the model control group and the cisplatin+YSP high-dose group,and 6 differentially expressed miRNAs between the cisplatin group and the cisplatin+YSP high-dose group.Biological function enrichment analysis showed that the differentially expressed miRNAs were mainly involved in the regulation of signaling pathways related to cell growth,proliferation,differentiation,autophagy and other biological activities.The miRNA-target gene regulatory network showed the top 20 genes that were targeted,among which there were proven miRNAs and genes related to lung cancer,and miRNAs that needed further investigation.The expression of miRNA-615-3p in tumor tissues decreased significantly in the cisplatin group and cisplatin+YSP high-dose group compared to that of the model group(P＜0.05 or P＜0.01).The miRNA-615-3p was negatively correlated with the survival prog-nosis of lung cancer(P＜0.05).Conclusion Cisplatin combined with YSP can effectively inhibit the proliferation of Lewis lung cancer tumors,and the tumor-suppressive effect is related to the regulation of multiple miRNAs,espe-cially the downregulation of miRNA-615-3p expression.
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