Background and Aims:The growing knowledge of ferroptosis has suggested the regulatory role of ferroptosis in hepatocellular carcinoma(HCC),but the pertinent molecular mechanisms remain unclear.Herein,this study invest...Background and Aims:The growing knowledge of ferroptosis has suggested the regulatory role of ferroptosis in hepatocellular carcinoma(HCC),but the pertinent molecular mechanisms remain unclear.Herein,this study investigated the mechanistic basis of ferroptosis-related genes(ferrGenes)in the growth of HCC.Methods:Differentially expressed human ferrGenes and tumor-related transcription factors(TFs)were obtained from the The Cancer Genome Atlas(TCGA)dataset and the GTEx dataset.Spearman method-based correlation analysis were conducted to construct TF-ferrGene coexpression regulatory network.Key genes associated with prognosis were singled out with Lasso regression and multivariate Cox analysis to construct the prognostic risk model.Then the accuracy and independent prognostic ability of the model were evaluated.Expression of CENPA and STMN1 was determined in clinical HCC tissues and HCC cells,and their binding was analyzed with dual-luciferase and chromatin immunoprecipitation(ChIP)assays.Furthermore,ectopic expression and knockdown assays were performed in HCC cells to assess the effect of CENPA and STMN1 on ferroptosis and malignant phenotypes.Results:The prognostic risk model constructed based on the eight TF-ferrGene regulatory network-related genes accurately predicted the prognosis of HCC patients.It was strongly related to the clinical characteristics of HCC patients.Moreover,CENPA/STMN1 might be a key TF-ferrGene regulatory network in ferroptosis of HCC.CENPA and STMN1 were overexpressed in HCC tissues and cells.Additionally,CENPA facilitated STMN1 transcription by binding to STMN1 promoter,thus facilitating the malignant phenotypes and suppressing the ferroptosis of HCC cells.Conclusions:Taken together,CENPA curbs the ferroptosis of HCC cells by upregulating STMN1 transcription,thereby promoting HCC growth.展开更多
着丝粒蛋白A(centromere protein A,CENPA)是组蛋白H3的特异性变体,在维持着丝粒染色质结构及确保染色体准确分离过程中发挥着重要作用。近年来的研究表明,CENPA在多种实体瘤中呈高表达状态,在乳腺癌中尤为显著。其异常上调不仅与肿瘤...着丝粒蛋白A(centromere protein A,CENPA)是组蛋白H3的特异性变体,在维持着丝粒染色质结构及确保染色体准确分离过程中发挥着重要作用。近年来的研究表明,CENPA在多种实体瘤中呈高表达状态,在乳腺癌中尤为显著。其异常上调不仅与肿瘤侵袭性增强密切相关,还参与染色体不稳定性及表观遗传调控网络的改变,从而促进肿瘤的发生与进展。本文在系统梳理CENPA在乳腺癌中表达特征、作用机制、预后价值及相关靶向治疗研究的基础上,概述近年的主要研究进展:在表达模式方面,明确其在不同分子分型中尤其是雌激素受体(estrogen receptor,ER)阴性与三阴性乳腺癌中的显著上调特征;在机制研究方面,揭示包括pRb缺失、MBNL1-AS1/ZFP36调控轴、FOXM1及其m6A修饰,以及PLA2R1/HHEX等多条信号转导通路在内的关键调控环节;在临床意义方面,研究显示,CENPA及其伴侣蛋白HJURP不仅可作为预后评估指标,还与内分泌治疗及化疗反应相关;在治疗探索方面,提出了针对Plk1的小分子抑制剂、抗CENPA单克隆抗体及RNA干扰等多种干预策略。综合分析现有研究结果,本文探讨CENPA在乳腺癌精准治疗中面临的机遇与挑战,为制订个体化治疗方案提供参考。展开更多
基金supported by Hunan Provincial Natural Science Foundation(2019JJ50321)Hunan Provincial Graduate Scientific Research Innovation Project(QL20220133).
文摘Background and Aims:The growing knowledge of ferroptosis has suggested the regulatory role of ferroptosis in hepatocellular carcinoma(HCC),but the pertinent molecular mechanisms remain unclear.Herein,this study investigated the mechanistic basis of ferroptosis-related genes(ferrGenes)in the growth of HCC.Methods:Differentially expressed human ferrGenes and tumor-related transcription factors(TFs)were obtained from the The Cancer Genome Atlas(TCGA)dataset and the GTEx dataset.Spearman method-based correlation analysis were conducted to construct TF-ferrGene coexpression regulatory network.Key genes associated with prognosis were singled out with Lasso regression and multivariate Cox analysis to construct the prognostic risk model.Then the accuracy and independent prognostic ability of the model were evaluated.Expression of CENPA and STMN1 was determined in clinical HCC tissues and HCC cells,and their binding was analyzed with dual-luciferase and chromatin immunoprecipitation(ChIP)assays.Furthermore,ectopic expression and knockdown assays were performed in HCC cells to assess the effect of CENPA and STMN1 on ferroptosis and malignant phenotypes.Results:The prognostic risk model constructed based on the eight TF-ferrGene regulatory network-related genes accurately predicted the prognosis of HCC patients.It was strongly related to the clinical characteristics of HCC patients.Moreover,CENPA/STMN1 might be a key TF-ferrGene regulatory network in ferroptosis of HCC.CENPA and STMN1 were overexpressed in HCC tissues and cells.Additionally,CENPA facilitated STMN1 transcription by binding to STMN1 promoter,thus facilitating the malignant phenotypes and suppressing the ferroptosis of HCC cells.Conclusions:Taken together,CENPA curbs the ferroptosis of HCC cells by upregulating STMN1 transcription,thereby promoting HCC growth.
文摘着丝粒蛋白A(centromere protein A,CENPA)是组蛋白H3的特异性变体,在维持着丝粒染色质结构及确保染色体准确分离过程中发挥着重要作用。近年来的研究表明,CENPA在多种实体瘤中呈高表达状态,在乳腺癌中尤为显著。其异常上调不仅与肿瘤侵袭性增强密切相关,还参与染色体不稳定性及表观遗传调控网络的改变,从而促进肿瘤的发生与进展。本文在系统梳理CENPA在乳腺癌中表达特征、作用机制、预后价值及相关靶向治疗研究的基础上,概述近年的主要研究进展:在表达模式方面,明确其在不同分子分型中尤其是雌激素受体(estrogen receptor,ER)阴性与三阴性乳腺癌中的显著上调特征;在机制研究方面,揭示包括pRb缺失、MBNL1-AS1/ZFP36调控轴、FOXM1及其m6A修饰,以及PLA2R1/HHEX等多条信号转导通路在内的关键调控环节;在临床意义方面,研究显示,CENPA及其伴侣蛋白HJURP不仅可作为预后评估指标,还与内分泌治疗及化疗反应相关;在治疗探索方面,提出了针对Plk1的小分子抑制剂、抗CENPA单克隆抗体及RNA干扰等多种干预策略。综合分析现有研究结果,本文探讨CENPA在乳腺癌精准治疗中面临的机遇与挑战,为制订个体化治疗方案提供参考。
