多囊卵巢综合征关键基因的筛选及其与疾病进展和预后的相关性分析  

Screening of key genes in polycystic ovary syndrome and analysis of their correlation with disease progression and prognosis

作　　者：孙奎奎 杨微微[2] 王文靖[2] 郝颖新 郭波 任晨春[2] 鞠明艳 SUN Kui-kui;YANG Wei-wei;WANG Wen-jing;HAO Ying-xin;GUO Bo;REN Chen-chun;JU Ming-yan(School of Gradute,Tianjin Medical University,Tianjin 300070,China;Department of Clinical Laboratory,Tianjin Central Hospital of Obstetrics and Gynecology,Tianjin 300100,China)

机构地区：[1]天津医科大学研究生院,天津300070 [2]天津市中心妇产科医院检验科,天津300100

出　　处：《天津医科大学学报》2023年第6期609-616,共8页Journal of Tianjin Medical University

基　　金：天津市卫生健康委员会科技项目(ZC20117);天津市医学重点学科(专科)建设项目(妇产科学TJYXZDXK-043A);天津市科技计划项目(21JCQNJC01860);天津市北辰区科技计划项目(SHGY-2022015)。

摘　　要：目的:通过生物信息学方法筛选多囊卵巢综合征(PCOS)的关键基因并分析其与PCOS进展和预后的相关性。方法:在GEO数据库中下载GSE34526数据集的表达谱,利用R软件筛选数据集中PCOS患者卵巢颗粒细胞(n=7)和正常颗粒细胞(n=3)的差异表达基因(DEGs),对DEGs进行基因本体论(GO)和京都百科全书基因和基因组(KEGG)富集分析,识别关键基因。使用单样本基因富集分析(ssGSEA)评分量化每个PCOS样本中的免疫信号的富集水平,进行抗肿瘤免疫和促肿瘤抑制评分。利用人类蛋白质图谱数据库(HPA)分析关键基因在卵巢癌(OC)、乳腺癌(BRCA)和子宫内膜癌(UCEC)中的蛋白表达水平,绘制ROC曲线分析3年、5年和10年癌症生存率。结果:本研究共筛选出16个DEGs,GO和KEGG分析结果显示DEGs在PCOS患者的细胞黏附分子(CAMs)、补体和凝血级联、上皮细胞迁移和炎症反应的正向调控等通路中富集,进一步筛选出2个关键基因,ITGAM和HMOX1。二者与促炎免疫细胞(如巨噬细胞、MDSCs、中性粒细胞、浆细胞样树突状细胞、调节性T细胞)的相关性分析显示,ITGAM(P分别为0.001、<0.001、0.051、0.04、<0.001)和HMOX1(P分别为<0.001、0.001、<0.001、<0.001、0.001)与以上促炎免疫细胞呈正相关,即发挥促炎作用。在OC、BRCA和UCEC组织中,ITGAM和HMOX1蛋白水平较高,而对照组无表达。作为不良预后因素,ITGAM显著影响PCOS继发的OC患者的生存(P=0.0046),ITGAM在OC中3、5、10年生存预测率ROC曲线下面积(AUC)均>0.5,其中10年AUC>0.59。HMOX1在BRCA、OC和UCEC中的3年AUC>0.5,在BRCA中的10年AUC>0.6,均有较好的预测效能。ITGAM+HMOX1联合预测在BRCA中的3、5、10年AUC分别为0.51、0.498、0.606,在OC中分别为0.563、0.537、0.481,在UCEC中分别为0.556、0.479、0.472。结论:ITGAM和HMOX1可以作为PCOS的潜在诊断和治疗靶点,其表达水平可以评价PCOS病情发展及预后。Objective:To screen key genes of polycystic ovary syndrome(PCOS)using bioinformatic analysis,and to explore their predictive effects on the progression and prognosis of PCOS.Methods:The expression profile of the GSE34526 dataset was downloaded from the GEO database,and the differential expression genes(DEGs)of ovarian granulosa cells(n=7)and normal granulosa cells(n=3)of PCOS patients in the dataset were screened using R software.Genetic Ontological(GO)and Kyoto Encyclopedia Gene and Genome(KEGG)enrichment analyses were performed on DEGs to identify key genes.A single-sample geneset enrichment analysis(ssGSEA)score was used to quantify the level of immune signal enrichment in each PCOS sample to perform anti-tumor immunity and pro-tumor inhibition scores.The Human Protein Profile Database(HPA)was used to analyze the protein expression levels of key genes in ovarian cancer(OC),breast cancer(BRCA)and uterine corpus endometrial cancer(UCEC).ROC curves were plotted to analyze the 3-year,5-year and 10-year cancer survival rates.Results:In this study,a total of 16 DEGs were screened.The results of GO and KEGG analysis showed that DEGs was enriched in the pathways of cell adhesion molecules(CAMs),complement and coagulation cascade,epithelial cell migration and positive regulation of inflammatory response in PCOS patients.Two key genes,ITGAM and HMOX1,were further screened.Correlation analysis between the two genes and pro-inflammatory immune cells(such as macrophages,MDSCs,neutrophils,plasmacytoid dendritic cells,regula tory T cells)showed that ITGAM(P values 0.001,<0.001,0.051,0.04,<0.001,respectively)and HMOX1(P values<0.001,0.001,<0.001,<0.001,<0.001,0.001,respectively)were positively correlated with the above pro-inflammatory immune cells,that was,they played a proinflammatory role.The levels of ITGAM and HMOX1 proteins were higher in OC,BRCA and UCEC tissues,but not in the control.As an adverse prognostic factor,ITGAM significantly affected the survival of OC patients secondary to PCOS(P=0.0046).The area under ROC

关 键 词：多囊卵巢综合征 生物信息学分析 ITGAM HMOX1 

分 类 号：R711[医药卫生—妇产科学]