目的研究KIAA0101在三阴性乳腺癌(triple-negative breast cancer,TNBC)中的表达及其对TNBC患者生存预后的影响。方法首先从GEO数据库筛选出TNBC芯片GSE38959和GSE27447,利用GEO2R对初始数据进行处理,以|logFC|>1、P<0.05为标准,...目的研究KIAA0101在三阴性乳腺癌(triple-negative breast cancer,TNBC)中的表达及其对TNBC患者生存预后的影响。方法首先从GEO数据库筛选出TNBC芯片GSE38959和GSE27447,利用GEO2R对初始数据进行处理,以|logFC|>1、P<0.05为标准,筛选出差异表达基因后进行GO富集分析。随后使用韦恩分析筛选出共同上调基因,并绘制柱状图确定最显著的上调基因,使用GEPIA数据库分析在TNBC癌组织中的表达水平,使用UALCAN数据库分析KIAA0101对临床病理分期分级的影响。使用TIMER数据库对KIAA0101与免疫细胞浸润联系进行分析。最后通过Kaplan-Meier Plotter数据库研究KIAA0101与TNBC进程的相关性及其对预后的影响。结果TNBC各个亚型组织样本中KIAA0101 mRNA显著升高,而且KIAA0101的mRNA表达水平与肿瘤的临床病理分期呈正相关趋势;KIAA0101与免疫细胞浸润正相关(P<0.05);KIAA0101高表达的TNBC患者总生存期较短,而低表达KIAA0101的患者总生存期较长(P<0.01)。结论KIAA0101在三阴性乳腺癌组织样本中高表达,与三阴性乳腺癌进展正相关,且不利于三阴性乳腺癌患者的总体生存预后,因此KIAA0101可以作为临床三阴乳腺癌患者潜在的诊治靶点或预后标志物。展开更多
Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reas...Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reasons for activation of KIAA1429(also known as VIRMA,an RNA methyltransferase)and its underlying mechanism in lung adenocarcinoma(LUAD)remain largely unexplored.In this study,we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.Methods:Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase.The in vitro and in vivo functions of KIAA1429 were investigated.Transcriptome sequencing,methylated RNA immunoprecipitation sequencing(MeRIP-seq),m6A dot blot assays and RNA immunoprecipitation(RIP)were performed to confirm the modified gene mediated by KIAA1429.RNA stability assays were used to detect the half-life of the target gene.Results:Copy number amplification drove higher expression of KIAA1429 in LUAD,whichwas correlatedwith poor overall survival.Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD.Mechanistically,the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays.We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner.Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA,leading to enhanced YTH m6A RNA binding protein 2(YTHDF2,the m6A“reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2;thus,participating in the tumorigenesis of LUAD.Conclusions:Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis,which may provide a novel view on the targeted molecular therapy of LUAD.展开更多
文摘目的研究KIAA0101在三阴性乳腺癌(triple-negative breast cancer,TNBC)中的表达及其对TNBC患者生存预后的影响。方法首先从GEO数据库筛选出TNBC芯片GSE38959和GSE27447,利用GEO2R对初始数据进行处理,以|logFC|>1、P<0.05为标准,筛选出差异表达基因后进行GO富集分析。随后使用韦恩分析筛选出共同上调基因,并绘制柱状图确定最显著的上调基因,使用GEPIA数据库分析在TNBC癌组织中的表达水平,使用UALCAN数据库分析KIAA0101对临床病理分期分级的影响。使用TIMER数据库对KIAA0101与免疫细胞浸润联系进行分析。最后通过Kaplan-Meier Plotter数据库研究KIAA0101与TNBC进程的相关性及其对预后的影响。结果TNBC各个亚型组织样本中KIAA0101 mRNA显著升高,而且KIAA0101的mRNA表达水平与肿瘤的临床病理分期呈正相关趋势;KIAA0101与免疫细胞浸润正相关(P<0.05);KIAA0101高表达的TNBC患者总生存期较短,而低表达KIAA0101的患者总生存期较长(P<0.01)。结论KIAA0101在三阴性乳腺癌组织样本中高表达,与三阴性乳腺癌进展正相关,且不利于三阴性乳腺癌患者的总体生存预后,因此KIAA0101可以作为临床三阴乳腺癌患者潜在的诊治靶点或预后标志物。
基金Science Fund for Creative Research Groups of the National Natural Science Foundation of China,Grant/Award Number:81521004National Natural Science Foundation of China,Grant/Award Numbers:81922061,82172992,81903391,81702266+2 种基金Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancers,Chinese Academy of Medical Sciences,Grant/Award Number:2019RU038Natural Science Foundation of Jiangsu Province,Grant/Award Numbers:BK20211253,BK20190148Postgraduate Research&Practice Innovation Program of Jiangsu Province,Grant/Award Number:KYCX18_0195。
文摘Background:Epigenetic alterations have been shown to contribute immensely to human carcinogenesis.Dynamic and reversible N6-methyladenosine(m6A)RNA modification regulates gene expression and cell fate.However,the reasons for activation of KIAA1429(also known as VIRMA,an RNA methyltransferase)and its underlying mechanism in lung adenocarcinoma(LUAD)remain largely unexplored.In this study,we aimed to clarify the oncogenic role of KIAA1429 in the tumorigenesis of LUAD.Methods:Whole-genome sequencing and transcriptome sequencing of LUAD data were used to analyze the gene amplification of RNA methyltransferase.The in vitro and in vivo functions of KIAA1429 were investigated.Transcriptome sequencing,methylated RNA immunoprecipitation sequencing(MeRIP-seq),m6A dot blot assays and RNA immunoprecipitation(RIP)were performed to confirm the modified gene mediated by KIAA1429.RNA stability assays were used to detect the half-life of the target gene.Results:Copy number amplification drove higher expression of KIAA1429 in LUAD,whichwas correlatedwith poor overall survival.Manipulating the expression of KIAA1429 could regulate the proliferation and metastasis of LUAD.Mechanistically,the target genes of KIAA1429-mediated m6A modification were confirmed by transcriptome sequencing and MeRIP-seq assays.We also revealed that KIAA1429 could regulate BTG2 expression in an m6A-dependent manner.Knockdown of KIAA1429 significantly decreased the m6A levels of BTG2 mRNA,leading to enhanced YTH m6A RNA binding protein 2(YTHDF2,the m6A“reader”)-dependent BTG2 mRNA stability and promoted the expression of BTG2;thus,participating in the tumorigenesis of LUAD.Conclusions:Our data revealed the activation mechanism and important role of KIAA1429 in LUAD tumorigenesis,which may provide a novel view on the targeted molecular therapy of LUAD.
