BACKGROUND Cancer stem cells(CSCs) have been implicated in tumorigenesis and tumor recurrence and metastasis are key therapeutic targets in cancer treatment.MicroRNAs display therapeutic potential by controlling the p...BACKGROUND Cancer stem cells(CSCs) have been implicated in tumorigenesis and tumor recurrence and metastasis are key therapeutic targets in cancer treatment.MicroRNAs display therapeutic potential by controlling the properties of CSCs;however, whether an association exists between miR-3682-3p and CSCs is unknown.AIM To investigate the mechanism by which miR-3682-3p promotes stemness maintenance in hepatocellular carcinoma(HCC).METHODS MiR-3682-3p expression in HCC cell lines and 34 pairs of normal and HCC specimens was assayed by quantitative polymerase chain reaction. The functional role of miR-3682-3p was investigated in vitro and in vivo. Dual-luciferase reporter and chromatin immunoprecipitation assays were performed for target assessment, and western blotting was utilized to confirm miR-3682-3p/target relationships.RESULTS We found that miR-3682-3p plays a key role in HCC pathogenesis by promoting HCC cell stemness. The upregulation of miR-3682-3p enhanced CSC spheroid-forming ability, side population cell fractions, and the expression of CSC factors in HCC cells in vitro and the tumorigenicity of transplanted HCC cells in vivo. Furthermore, silencing miR-3682-3p prolonged the survival of HCC-bearing mice. Mechanistically, we found that miR-3682-3p targets FOXO3 and enables FOXO3/β-catenin interaction, which promotes c-Myc expression through PI3K/AKT;cMyc, in turn, activates miR-3682-3p, forming a positive feedback loop. Intriguingly, miR-3682-3p expression was induced by hepatitis B virus X protein(HBx) and was involved in HBx-induced tumor stemness-related pathogenesis.CONCLUSION Our findings reveal a novel mechanism by which miR-3682-3p promotes stemness in HCC stem cells. Silencing miR-3682-3p may represent a novel therapeutic strategy for HCC.展开更多
叉头框蛋白O3a(fork head box O3a,FoxO3a)是叉头框蛋白FOX转录因子O亚型家族中成员,作为一种转录调节因子在多种疾病的发生与发展中发挥重要调节作用。线粒体是细胞能量代谢的主要场所,也是维持细胞生长和功能的一类关键细胞器。线粒...叉头框蛋白O3a(fork head box O3a,FoxO3a)是叉头框蛋白FOX转录因子O亚型家族中成员,作为一种转录调节因子在多种疾病的发生与发展中发挥重要调节作用。线粒体是细胞能量代谢的主要场所,也是维持细胞生长和功能的一类关键细胞器。线粒体功能受到多种转录因子调控。FoxO3a可定位于线粒体,通过调节细胞核与线粒体之间的相互作用,对线粒体功能产生重要影响,其机制与调节线粒体能量代谢、生物合成、自噬、分裂/融合,以及线粒体钙稳态密切相关。该文重点综述了FoxO3a的生物学功能、及其对线粒体的调控作用与机制。展开更多
基金Supported by the 12~(th) Special Fund for Young Scientists and Technicians in Guizhou Province,No.(2019) 5647the Science and Technology Fund of Guizhou Provincial Health and Health Commission,No.gzwjkj2020-1-101+1 种基金the National Natural Science Foundation Training Program of Guizhou Medical University,No.19NSP055Dongguan Science and Technology of Social Development Program,No.201950715024201
文摘BACKGROUND Cancer stem cells(CSCs) have been implicated in tumorigenesis and tumor recurrence and metastasis are key therapeutic targets in cancer treatment.MicroRNAs display therapeutic potential by controlling the properties of CSCs;however, whether an association exists between miR-3682-3p and CSCs is unknown.AIM To investigate the mechanism by which miR-3682-3p promotes stemness maintenance in hepatocellular carcinoma(HCC).METHODS MiR-3682-3p expression in HCC cell lines and 34 pairs of normal and HCC specimens was assayed by quantitative polymerase chain reaction. The functional role of miR-3682-3p was investigated in vitro and in vivo. Dual-luciferase reporter and chromatin immunoprecipitation assays were performed for target assessment, and western blotting was utilized to confirm miR-3682-3p/target relationships.RESULTS We found that miR-3682-3p plays a key role in HCC pathogenesis by promoting HCC cell stemness. The upregulation of miR-3682-3p enhanced CSC spheroid-forming ability, side population cell fractions, and the expression of CSC factors in HCC cells in vitro and the tumorigenicity of transplanted HCC cells in vivo. Furthermore, silencing miR-3682-3p prolonged the survival of HCC-bearing mice. Mechanistically, we found that miR-3682-3p targets FOXO3 and enables FOXO3/β-catenin interaction, which promotes c-Myc expression through PI3K/AKT;cMyc, in turn, activates miR-3682-3p, forming a positive feedback loop. Intriguingly, miR-3682-3p expression was induced by hepatitis B virus X protein(HBx) and was involved in HBx-induced tumor stemness-related pathogenesis.CONCLUSION Our findings reveal a novel mechanism by which miR-3682-3p promotes stemness in HCC stem cells. Silencing miR-3682-3p may represent a novel therapeutic strategy for HCC.
文摘目的研究血管内皮细胞在冠状动脉疾病中的作用,着重阐明转录因子叉头框蛋白O3a(forkhead box O3a,FOXO3a)调控靶标基因表达和可变剪接在血管内皮细胞损伤中的作用。方法通过在人血管内皮细胞系中过表达FOXO3a,利用转录组技术获得转录组数据。分析FOXO3a调控的潜在靶标基因的表达水平和可变剪接模式,以及这些基因的功能。结果FOXO3a过表达的HUVEC细胞中,与对照组比较,419个基因差异表达。基因本体论(gene ontology,GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)分析结果显示,上调基因富集在炎性信号通路,下调基因富集在代谢通路。基于转录组数据进行可变剪切分析,发现1784个可变剪切事件的模式在FOXO3a过表达组和对照组间发生显著差异。GO和KEGG分析结果显示,差异可变剪切基因富集在细胞凋亡相关通路。结论FOXO3a通过调控免疫炎症、脂类代谢和细胞凋亡相关基因的表达和可变剪接,影响血管内皮细胞凋亡,可能影响冠心病的发生。
文摘叉头框蛋白O3a(fork head box O3a,FoxO3a)是叉头框蛋白FOX转录因子O亚型家族中成员,作为一种转录调节因子在多种疾病的发生与发展中发挥重要调节作用。线粒体是细胞能量代谢的主要场所,也是维持细胞生长和功能的一类关键细胞器。线粒体功能受到多种转录因子调控。FoxO3a可定位于线粒体,通过调节细胞核与线粒体之间的相互作用,对线粒体功能产生重要影响,其机制与调节线粒体能量代谢、生物合成、自噬、分裂/融合,以及线粒体钙稳态密切相关。该文重点综述了FoxO3a的生物学功能、及其对线粒体的调控作用与机制。
