仑伐替尼对肝细胞癌组织中肿瘤相关成纤维细胞自噬和迁移的影响

EFFECT OF LENVATINIB ON THE AUTOPHAGY AND MIGRATION OF CANCER-ASSOCIATED FIBROBLASTS IN HEPATOCELLULAR CARCINOMA TISSUE

目的 探讨仑伐替尼对于肝细胞癌(hepatocellular carcinoma, HCC)组织中肿瘤相关成纤维细胞(CAFs)自噬和迁移的影响。方法 分离并培养HCC患者肿瘤组织中原代CAFs,分别使用等体积的DMSO和46 nmol/L的仑伐替尼处理72 h,分为DMSO组和仑伐替尼组,对两组细胞进行转录组学测序分析和药物靶点组学分析,对差异表达基因和差异表达肽段进行GO功能和KEGG信号通路富集分析;使用透射电镜观察仑伐替尼对CAF自噬的影响,通过Transwell和划痕实验检测仑伐替尼对CAFs迁移能力的影响。结果 DMSO组与仑伐替尼组之间的差异表达基因和差异肽段主要富集在细胞迁移、自噬等相关功能和通路上;透射电镜观察显示,仑伐替尼组CAFs的自噬小体明显多于DMSO组(t=5.376,P<0.05),Transwell和划痕实验结果显示,仑伐替尼组CAFs迁移能力明显弱于DMSO组(t=10.31、14.33,P<0.05)。结论 仑伐替尼可诱导HCC组织中CAFs自噬,并抑制其迁移。

Objective To investigate the effect of lenvatinib on the autophagy and migration of cancer-associated fibroblasts(CAFs)in hepatocellular carcinoma(HCC)tissue.Methods Primary CAFs from HCC patients were isolated and cultured and were then treated with an equal volume of DMSO(DMSO group)or 46 nmol/L lenvatinib(lenvatinib group)for 72 h.Transcriptomic sequencing and the omics analysis of drug targets were performed for the two groups,and GO functional enrichment analysis and KEGG pathway enrichment analysis were performed for differentially expressed genes and peptides.Transmission electron microscopy was used to observe the effect of lenvatinib on autophagy of CAFs,and Transwell assay and wound hea-ling assay were used to observe the effect of lenvatinib on the migration ability of CAFs.Results The differentially expressed genes and peptides between the DMSO group and the lenvatinib group were mainly enriched in the functions and pathways such as cell migration and autophagy.Transmission electron microscopy showed that the lenvatinib group had a significantly higher number of autophagosomes than the DMSO group(t=5.376,P<0.05),and Transwell assay and wound healing assay showed that the lenvatinib group had a significantly weaker migration ability than the DMSO group(t=10.31,14.33,P<0.05).Conclusion Lenvatinib can induce the autophagy of CAFs and inhibit their migration in HCC tissue.