MZB1的可变剪接事件是乳腺癌内分泌治疗耐药的潜在生物标志物  

The alternative splicing event of MZB1 is a potential biomarker of drug resistance in endocrine therapy of breast cancer

作　　者：张宇晴 荆晶 刘兆良 安静 安巍巍 ZHANG Yuqing;JING Jing;LIU Zhaoliang;AN Jing;AN Weiwei(Institute of Cancer Prevention and Treatment,Harbin Medical University,Harbin 150081,China;Department of Radiology,Harbin Medical University Cancer Hospital)

机构地区：[1]哈尔滨医科大学肿瘤防治研究所,哈尔滨150081 [2]哈尔滨医科大学附属肿瘤医院放疗科

出　　处：《实用肿瘤学杂志》2024年第5期313-322,共10页Practical Oncology Journal

基　　金：黑龙江省自然科学基金联合引导项目(编号:LH2020H111)。

摘　　要：目的利用生物信息学方法,整合基因表达谱和剪接谱,鉴定在内分泌治疗耐药中发挥作用的潜在生物标志物。方法从基因表达综合数据库(Gene expression omnibus,GEO)下载内分泌治疗敏感细胞和耐药细胞的基因数据集,筛选与内分泌治疗耐药相关的差异表达基因和差异剪接基因,并对这些基因进行Hallmark富集分析和基因集富集分析(Gene set enrichment analysis,GSEA)。下载癌症基因组图谱(The cancer genome atlas,TCGA)和乳腺癌国际联盟分子分类数据库(Molecular taxonomy of breast cancer international consortium,METABRIC)中的乳腺癌数据,比较差异基因在肿瘤组织和癌旁组织中的表达情况以及在不同肿瘤分期、分级之间的差异。探索差异基因与接受内分泌治疗患者的总生存期(Overall survival,OS)的关系及其可变剪接情况以及免疫浸润情况。结果GEO数据分析显示,差异表达基因主要富集在乳腺癌治疗反应相关通路和免疫相关通路,差异剪接基因主要富集在乳腺癌治疗反应相关通路。同时发生差异表达和差异剪接的基因有CAMK2B、EVL、MZB1和PTPRG。其中,MZB1表达与接受内分泌治疗患者的OS以及免疫细胞浸润均相关,且在耐药细胞中MZB1的前体mRNA发生更多的可变3′端剪接。结论MZB1表达与乳腺癌内分泌治疗疗效相关,其机制可能是通过发生可变剪接引起免疫相关功能的改变。MZB1可作为内分泌治疗改善预后的潜在生物标志物。Objective The aim of this study was to use bioinformatics methods to integrate gene expression profiles and splicing profiles,and identify potential biomarkers that play a role in endocrine therapy resistance.Methods The gene datasets of endocrine therapy sensitive and resistant cells from the Gene expression omnibus(GEO)database were downloaded to screen for differentially expressed genes and differential splicing genes related to endocrine therapy resistance,and perform Hallmark enrichment analysis and Gene set enrichment analysis(GSEA)on these genes.The cancer genome atlas(TCGA)and the breast cancer data in the Molecular taxonomy of breast cancer international consortium(METABRIC)were downloaded,and compared the expression of differential genes in tumor and adjacent tissues,as well as the differences between different tumor stages and grades.The relationship between differential expressed genes and overall survival(OS),alternative splicing,and immune infiltration were explored in patients receiving endocrine therapy.Results GEO data analysis showed that differentially expressed genes were mainly enriched in breast cancer treatment response related to pathways and immune-related pathways,and differentially spliced genes were mainly enriched in breast cancer treatment response related to pathways.The genes that undergo differential expression and splicing simultaneously included CAMK2B,EVL,MZB1and PTPRG.Among them,the expression of MZB1 was associated with OS and immune cell infiltration in patients receiving endocrine therapy,and the precursor mRNA of MZB1 underwent more alternative 3′splicing in drug-resistant cells.Conclusion The expression of MZB1 is related to the effect on endocrine therapy in breast cancer,and its mechanism may be the change of immune related function caused by alternative splicing.MZB1 can serve as a potential biomarker for endocrine therapy to improve prognosis.

关 键 词：乳腺癌 内分泌治疗 可变剪接 免疫浸润 

分 类 号：R737.9[医药卫生—肿瘤]