组蛋白去乙酰化酶抑制剂通过调节VEGF通路影响弥漫性大B细胞淋巴瘤进程机制研究

Histone deacetylase inhibitors suppress the progression of diffuse large B cell lymphoma by regulating the VEGF pathway

该研究旨在揭示组蛋白去乙酰化酶抑制剂ST7612AA1对弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)细胞增殖和血管生成的影响及其机制,为DLBCL寻找新的有效治疗方法。通过生物信息学筛选出ST7612AA1处理的DLBCL细胞的差异基因及通路情况。进一步通过甲基四氮唑盐(methyl tetrazolium salt,MTS)和血管生成试验测定ST7612AA1对DLBCL的增殖和血管形成的影响。通过qRT-PCR检测血管内皮生长因子(vascular endothelial growth factor,VEGF)A/C/D mRNA的水平;并使用Western blotting分析评估VEGF信号通路的蛋白表达。该研究对GSE62460数据分析发现ST7612AA1处理后DLBCL细胞中VEGFA表达显著下调。经过基因集富集分析(gene set enrichment analysis,GSEA),发现ST7612AA1暴露后VEGF信号通路被抑制。进一步细胞活力检测发现DLBCL细胞的增殖被ST7612AA1显著抑制(P<0.05)。此外,与其他组相比,ST7612AA1能够显著抑制DLBCL的血管形成作用(P<0.05)。ST7612AA1处理后,VEGF信号通路中基因和蛋白水平显著降低,通路被抑制(P<0.05)。综上,该研究发现ST7612AA1通过抑制VEGF信号通路抑制DLBCL细胞增殖和血管生成作用。

The purpose of this study was to reveal the effect and mechanism of histone deacetylase inhibitor ST7612AA1 on the proliferation and angiogenesis of diffuse large B cell lymphoma(DLBCL)cells,and to find new and effective treatments for DLBCL.The differentially expressed genes and pathways of ST7612AA1-treated DLBCL cells were analyzed by bioinformatics.The effect of ST7612AA1 on the proliferation and angiogenesis of DLBCL was further examined by methyl tetrazolium salt(MTS)treatment and angiogenesis assay.The mRNA levels of vascular endothelial growth factor(VEGF)A/C/D were detected by qRT-PCR.The protein expressions of the VEGF signaling pathway were measured by Western blotting.The bioinformatic analysis on the GSE62460 dataset showed that VEGFA expression was significantly down-regulated in DLBCL cells after ST7612AA1 treatment.Gene set enrichment analysis(GSEA)found that the VEGF signaling pathway was inhibited upon ST7612AA1 treatment.Further cell viability test found that the proliferation of DLBCL cells was significantly inhibited by ST7612AA1 treatment(P<0.05).In addition,compared to other treatments,ST7612AA1 significantly inhibited the angiogenesis of DLBCL(P<0.05).After ST7612AA1 treatment,the levels of genes and proteins involved in the VEGF signaling pathway were significantly decreased,thus inhibiting the signal transduction(P<0.05).In conclusion,our results show that ST7612AA1 suppresses the proliferation and angiogenesis of DLBCL cells by inhibiting the VEGF signaling pathway.