目的分析SH3BP2基因点突变后,与其相关的信号转导通路发生的变化,探讨巨颌症发病的分子机制。方法采用免疫荧光技术检测巨颌症患者的活化T细胞核因子(nuclear factor of activated Tcells,NFAT)家族中的NFATc1及SH3BP2蛋白在细胞内的定...目的分析SH3BP2基因点突变后,与其相关的信号转导通路发生的变化,探讨巨颌症发病的分子机制。方法采用免疫荧光技术检测巨颌症患者的活化T细胞核因子(nuclear factor of activated Tcells,NFAT)家族中的NFATc1及SH3BP2蛋白在细胞内的定位及表达含量的变化。结果巨颌症标本中NFATc1总体表达含量变化不明显,但发生了核内转位;SH3BP2在巨颌症组织中表达量增高。结论巨颌症致病基因SH3BP2发生点突变后,SH3BP2蛋白表达量可增多,并可导致NFATc1发生核内转位,这可能是导致巨颌症病变中破骨细胞被激活,形成骨吸收的重要机制。展开更多
Background:Increased Galectin 3-binding protein(LGALS3BP)serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma(HCC).Considering the crucial role of transforming gro...Background:Increased Galectin 3-binding protein(LGALS3BP)serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma(HCC).Considering the crucial role of transforming growth factor-β1(TGF-β1)in the emergence of these diseases,the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway.Methods:The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis(MASH)and HCC.Multiple omics techniques,such as RNA-sequencing,transposaseaccessible chromatin-sequencing assay,and liquid chromatography-tandem mass spectrometry proteomics,were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis.The effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional LGALS3BP-knockin and LGALS3BP-knockout mice.Results:In patients with MASH and HCC,the levels of LGALS3BP and TGFB1 exhibited positive correlations.Stimulation of LGALS3BP by the inflammatory cytokine interferonαin HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1.Aggravated fibrosis was observed in the livers of hepatocyte-specific LGALS3BP-knockin mice,with increased TGFB1 levels.LGALS3BP directly bound to and assembled integrinαV,an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton.The released TGF-β1 activated JunB transcription factor,which in turn promoted the TGF-β1 positive feedback loop.LGALS3BP deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis.Moreover,LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1.Conclusion:LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway,making it a promising therapeutic target in TGF-β1-related diseases.展开更多
目的检测分析异染色质蛋白1结合蛋白3(heterochromatin protein 1 binding protein 3,HP1BP3)在肝细胞癌中的表达及其对细胞恶性生物学行为的影响。方法应用TCGA数据库分析肝细胞癌与癌旁组织中HP1BP3基因的表达差异。生存检验分析HP1BP...目的检测分析异染色质蛋白1结合蛋白3(heterochromatin protein 1 binding protein 3,HP1BP3)在肝细胞癌中的表达及其对细胞恶性生物学行为的影响。方法应用TCGA数据库分析肝细胞癌与癌旁组织中HP1BP3基因的表达差异。生存检验分析HP1BP3表达与肝细胞癌患者总生存期的关系,单因素及多因素分析相关危险因素。应用Western blot和免疫组化法检测HP1BP3蛋白表达水平。用小干扰RNA(siRNA)分别转染Huh7、HepG2细胞,功能实验检测细胞增殖、迁移和侵袭能力。通过GSEA分析对其作用机制进行探究。结果TCGA数据库分析结果显示,HP1BP3基因在肝细胞癌组织中的表达明显高于非肿瘤组织(P<0.01),高表达组患者的总生存期较低表达组短(P=0.029)。HP1BP3基因是肝细胞癌的独立预测因子(P=0.024)。体外实验结果显示,HP1BP3基因在肝癌细胞株及肝细胞癌组织中表达上调。沉默HP1BP3基因可抑制肝癌细胞的增殖、侵袭和迁移。HP1BP3高表达与泛素化(P<0.001)、核酸切除修复(P<0.001)、RNA降解(P<0.001)、ERBB信号通路(P<0.001)、细胞周期(P<0.001)、细胞凋亡(P<0.001)通路有关。结论HP1BP3基因在肝细胞癌组织中表达上调,是肝细胞癌独立的预后危险因素,可促进肝细胞癌的发生、发展。展开更多
文摘目的分析SH3BP2基因点突变后,与其相关的信号转导通路发生的变化,探讨巨颌症发病的分子机制。方法采用免疫荧光技术检测巨颌症患者的活化T细胞核因子(nuclear factor of activated Tcells,NFAT)家族中的NFATc1及SH3BP2蛋白在细胞内的定位及表达含量的变化。结果巨颌症标本中NFATc1总体表达含量变化不明显,但发生了核内转位;SH3BP2在巨颌症组织中表达量增高。结论巨颌症致病基因SH3BP2发生点突变后,SH3BP2蛋白表达量可增多,并可导致NFATc1发生核内转位,这可能是导致巨颌症病变中破骨细胞被激活,形成骨吸收的重要机制。
基金Bio&Medical Technology Development Program of the National Research Foundation,Grant/Award Numbers:NRF-2020M3A9G3080281,NRF-2020R1A5A2031185Korean Government。
文摘Background:Increased Galectin 3-binding protein(LGALS3BP)serum levels have been used to assess hepatic fibrosis stages and the severity of hepatocellular carcinoma(HCC).Considering the crucial role of transforming growth factor-β1(TGF-β1)in the emergence of these diseases,the present study tested the hypothesis that LGALS3BP regulates the TGF-β1 signaling pathway.Methods:The expression levels of LGALS3BP and TGFB1 were analyzed in patients with metabolic dysfunction-associated steatohepatitis(MASH)and HCC.Multiple omics techniques,such as RNA-sequencing,transposaseaccessible chromatin-sequencing assay,and liquid chromatography-tandem mass spectrometry proteomics,were used to identify the regulatory mechanisms for the LGALS3BP-TGF-β1 axis.The effects of altered TGF-β1 signaling by LGALS3BP were investigated in conditional LGALS3BP-knockin and LGALS3BP-knockout mice.Results:In patients with MASH and HCC,the levels of LGALS3BP and TGFB1 exhibited positive correlations.Stimulation of LGALS3BP by the inflammatory cytokine interferonαin HCC cells or ectopic overexpression of LGALS3BP in hepatocytes promoted the expression levels of TGFB1.Aggravated fibrosis was observed in the livers of hepatocyte-specific LGALS3BP-knockin mice,with increased TGFB1 levels.LGALS3BP directly bound to and assembled integrinαV,an integral mediator required for releasing active TGF-β1 from extracellular latent complex with the rearranged F-actin cytoskeleton.The released TGF-β1 activated JunB transcription factor,which in turn promoted the TGF-β1 positive feedback loop.LGALS3BP deletion in the hepatocytes downregulated TGF-β1 signaling and CCl4 induced fibrosis.Moreover,LGALS3BP depletion hindered hepatocarcinogenesis by limiting the availability of fibrogenic TGF-β1.Conclusion:LGALS3BP plays a crucial role in hepatic fibrosis and carcinogenesis by controlling the TGF-β1 signaling pathway,making it a promising therapeutic target in TGF-β1-related diseases.
文摘目的检测分析异染色质蛋白1结合蛋白3(heterochromatin protein 1 binding protein 3,HP1BP3)在肝细胞癌中的表达及其对细胞恶性生物学行为的影响。方法应用TCGA数据库分析肝细胞癌与癌旁组织中HP1BP3基因的表达差异。生存检验分析HP1BP3表达与肝细胞癌患者总生存期的关系,单因素及多因素分析相关危险因素。应用Western blot和免疫组化法检测HP1BP3蛋白表达水平。用小干扰RNA(siRNA)分别转染Huh7、HepG2细胞,功能实验检测细胞增殖、迁移和侵袭能力。通过GSEA分析对其作用机制进行探究。结果TCGA数据库分析结果显示,HP1BP3基因在肝细胞癌组织中的表达明显高于非肿瘤组织(P<0.01),高表达组患者的总生存期较低表达组短(P=0.029)。HP1BP3基因是肝细胞癌的独立预测因子(P=0.024)。体外实验结果显示,HP1BP3基因在肝癌细胞株及肝细胞癌组织中表达上调。沉默HP1BP3基因可抑制肝癌细胞的增殖、侵袭和迁移。HP1BP3高表达与泛素化(P<0.001)、核酸切除修复(P<0.001)、RNA降解(P<0.001)、ERBB信号通路(P<0.001)、细胞周期(P<0.001)、细胞凋亡(P<0.001)通路有关。结论HP1BP3基因在肝细胞癌组织中表达上调,是肝细胞癌独立的预后危险因素,可促进肝细胞癌的发生、发展。
