基于差异基因网络特性探究乳腺癌他莫昔芬耐药的关键标志物  

Identification of tamoxifen resistance-related crucial genes based on network features of differential expression genes

作　　者：马军 王雪庭 陈梦杰 孟磊[3] 王乐[4] MA Jun;WANG Xue-ting;CHEN Meng-jie;MENG Lei;WANG Le(School of Food and Biological Engineering,Shaanxi University of Science&Technology,Xi′an 710021,China;State Key Laboratory of Applied Microbiology in Southern China,Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application,Guangdong Open Laboratory of Applied Microbiology,Guangdong Institute of Microbiology,Guangdong Academic of Science,Guangzhou 510070,China;Department of Surgical Oncology,the First Affiliated Hospital of Xi′an Jiaotong University,Xi′an 710061,China;Department of Oncology,the First Affiliated Hospital of Xi′an Jiaotong University,Xi′an 710061,China)

机构地区：[1]陕西科技大学食品与生物工程学院,陕西西安710021 [2]广东省科学院广东省微生物研究所省部共建华南应用微生物国家重点实验室广东省菌种保藏与应用重点实验室广东省微生物应用新技术公共实验室,广东广州510070 [3]西安交通大学第一附属医院肿瘤外科,陕西西安710061 [4]西安交通大学第一附属医院肿瘤内科,陕西西安710061

出　　处：《陕西科技大学学报》2020年第5期67-74,共8页Journal of Shaanxi University of Science & Technology

基　　金：中国博士后科学基金项目(2020M673605XB);陕西科技大学博士科研启动基金项目(126021975)。

摘　　要：他莫昔芬适用于绝经前或绝经后的患者,能有效降低雌激素受体阳性(estrogen receptor positive,ER+)患者的死亡率和复发率,目前仍然是乳腺癌内分泌治疗的基础用药,然而在临床应用中已经发现约半数患者出现原发或继发性他莫昔芬耐药.因此,鉴定有效的他莫昔芬耐药关键基因将为TAM治疗ER+的乳腺癌患者提供重要的参考价值.本文首先联合Cancer Cell Line Encyclopedia(CCLE)数据库中的乳腺癌细胞系表达谱和STRING数据库中人类蛋白相互作用数据,得到了基于乳腺癌的蛋白互作(breast cancer-based PPI,B_PPI)网络.再通过walktrap算法对B_PPI网络中的基因进行聚类分析,产生不同大小的群落.同时,收集并分析GEO(Gene Expression Omnibus)数据库中与他莫昔芬耐药相关的乳腺癌转录组数据,从而得到表达差异基因.再用reciprocal best-hit方法对群落与表达差异基因进行相似性分析找出与他莫昔芬耐药相关的群落.依据群落的功能特性和差异基因网络特性筛选耐药核心基因.最后选用核心基因STAT1和CDH1作为示例,探究基因表达情况与预后的关系.构建了包含7904个基因和213422个连接数的乳腺癌蛋白互作网络.经预后标记物验证发现CW4、CW5、CW13、CW21和CW33群落(共3863个基因)与他莫昔芬耐药相关,且CW5的显著性最高.功能分析发现CW5中基因参与丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)信号通路.选取前5个具有高节点度的表达差异基因STAT3、STAT1、CDH1、EGR1和PRKCA作为TAM耐药的核心基因,并通过他莫昔芬治疗后预后数据及文献证据验证核心基因表达与他莫昔芬耐药密切相关.耐药核心基因的表达情况与他莫昔芬治疗ER+乳腺癌患者的疗效关系密切.表达差异基因网络特性可以用于筛选乳腺癌他莫昔芬耐药的关键基因.Tamoxifen(TAM),as the first-line treatment of breast cancer,plays an important role in reducing the mortality and recurrence rate of ER+patients.However,about half of ER positive patients are primary and acquired tamoxifen resistant.Therefore,the identification of effective tamoxifen resistance-related crucial genes will provide an important clue for the response after ER+breast cancer patients treated with TAM.In this paper,we firstly integrate the expression profile of breast cancer cell line in Cancer Cell Line Encyclopedia(CCLE)database with the data of human protein interaction in string database to build breast cancer-based PPI,B_PPI)network.Then,we performed a cluster analysis for B-based PPI network using Walktrap algorithm and generated modules with various sizes.Meanwhile,we compared the gene expression profiles of TAM and TAM resistance groups to find the differential expression genes.To find the significantly TAM resistance-correlated modules,the similarity of modules and list of differential expression genes were evaluated by reciprocal best-hit approach.Crucial genes related to TAM resistance were identified by integrating functional characteristics of the modules,differential expression genes with network features of genes.Finally,STAT1 and CDH1 were used as examples to explore the relationship between gene expression and prognosis.Breast cancer-based PPI network includes 7904 genes and 213422 interactions by integrating original PPI network with expressed genes in breast cancer cell lines.We find 3863 genes involved in CW4,CW5,CW13,CW21 and CW33 are closely correlate with tamoxifen resistance and validated by prognostic genes.CW5 is one of them mostly significantly modules and participates to several cancer related pathways,such as mitogen-activated protein kinase,MAPK single pathway.Top 5 differentially expressed genes,including STAT3,STAT1,CDH1,EGR1 and PRKCA,with highly degree in CW5 module were considered as hub genes of tamoxifen resistance based on the clinical data produced by breast cancer

关 键 词：蛋白与蛋白互作网络 乳腺癌 他莫昔芬耐药 预后标记物 差异基因 

分 类 号：R737.9[医药卫生—肿瘤]