剪接体LSM4通过调控DNA损伤修复途径抑制三阴性乳腺癌细胞MDA-MB-231恶性进展OA
Spliceosome LSM4 inhibits the malignant progression of triple-negative breast cancer cell MDA-MB-231 through regulating DNA damage repair pathway
目的 探索剪接体蛋白 LSM4 在三阴性乳腺癌(TNBC)中的生物学功能及潜在的调控机制.方法 使用癌基因组图谱(TCGA)和临床蛋白质组学肿瘤分析协会(CPTAC)样本分析 LSM4 在 TNBC 中的 mRNA 和蛋白表达水平,采用小干扰 RNA(siRNA)在 MDA-MB-231 细胞中瞬时敲低 LSM4,CCK-8法检测细胞增殖,Annexin V/PI 法检测细胞凋亡,Transwell 实验检测细胞的侵袭和迁移,转录组测序(RNA-seq)分析 LSM4 调控的差异表达基因和可变剪接事件.结果 LSM4 在 TNBC 患者中表达失调,体外敲低 LSM4 后可显著促进 MDA-MB-231 细胞的增殖、侵袭和迁移能力,并抑制细胞凋亡,LSM4 调控的可变剪接基因主要富集在与 DNA 损伤修复相关的信号途径上,特别是参与调节 DNA 聚合酶 β(POLB)的外显子互斥和跳跃事件,可能促使其生成非编码蛋白或编码较短蛋白的转录本异构体,从而影响癌细胞基因组稳定性.结论 LSM4 可能通过激活并调控 DNA 损伤修复途径相关基因的可变剪接事件从而影响 TNBC 的发生和发展.
Objective To explore the biological functions and potential regulatory mechanisms of spliceosome LSM4 in triple-negative breast cancer(TNBC).Methods The mRNA and protein expression levels of LSM4 in TNBC were analyzed using The Cancer Genome Atlas(TCGA)and Clinical Proteomics Tumor Analysis Consortium(CPTAC)samples,and small interfering RNA(siRNA)was used to transiently knock down LSM4 in MDA-MB-231 cells.CCK-8 assay for cell proliferation,annexin V/PI double staining for apoptosis,Transwell to detect cell invasion and migration,and RNA-seq to analyze the differentially expressed genes and regulated alternative splicing events.Results LSM4 was abnormally expressed in TNBC patients,and knockdown of LSM4 in vitro significantly promoted the proliferation,invasion and migration of MDA-MB-231 cells and inhibited apoptosis.The alternative splicing genes regulated by LSM4 were mainly enriched in the signaling pathways related to DNA damage repair,especially involved in modulating the exon exclusion and skipping events of DNA polymerase β(POLB),possibly promoting the generation of transcript isoforms with non-coding or encoding for a shorter protein,thereby affecting the genomic stability of cancer cells.Conclusions LSM4 might affect the onset and progression of TNBC via activa-ting and modulating alternative splicing events of genes involved in DNA damage repair pathway.
孜那提·努尔太;柔倩;张梦;刘莹;成芳
新疆医科大学 医学科学研究所,新疆 乌鲁木齐 830017||新疆医科大学附属肿瘤医院 综合特需科,新疆 乌鲁木齐 830000新疆医科大学附属肿瘤医院 综合特需科,新疆 乌鲁木齐 830000新疆医科大学附属肿瘤医院 综合特需科,新疆 乌鲁木齐 830000新疆医科大学附属肿瘤医院 综合特需科,新疆 乌鲁木齐 830000新疆医科大学附属肿瘤医院 综合特需科,新疆 乌鲁木齐 830000
医药卫生
LSM4三阴性乳腺癌转录组测序可变剪接DNA损伤与修复
LSM4triple negative breast cancerRNA-seqalternative splicingDNA damage and repair
《基础医学与临床》 2026 (10)
1366-1374,9
新疆医科大学医学科学研究所开放课题(YXYJ20240304)
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