前列腺癌多组学基因筛选及分析

Screening and analysis of core genes in prostate cancer

目的探讨与前列腺癌发生进展有关的核心基因及其调控网络。方法获取2018年11月1日至2018年12月31日在癌症基因组图谱(TCGA)数据库下载的495例前列腺癌和52例对照样本的基因表达数据、498例前列腺癌和50例对照样本的甲基化芯片数据、494例前列腺癌和52例对照样本的miRNA表达谱数据,核对及更新于2020年12月1日至2020年12月30日,整合NCBI-gene和OMIM上的前列腺癌相关基因,构建前列腺癌致病基因表达谱矩阵,包括编码蛋白基因、非编码基因及甲基化基因,并进行差异分析、共表达网络及pivot分析。结果共筛选出1083个差异表达的蛋白编码基因,筛选出149个差异lncRNA。挖掘到9个模块,与前列腺癌最相关的模块是棕色和青绿色模块(均P<0.001)。青绿色模块可以将样本分成两个聚类,两个聚类中的前列腺癌样本数比较,差异有统计学意义(163例vs.332例,P<0.05)。富集分析发现青绿色模块基因与细胞黏附、细胞迁移等生物学过程有关,这些基因参与了转化生长因子-β(TGF-β)、过氧化物酶体增殖剂激活受体(PPAR)信号通路,与是否患病具有相关性(P<0.05)。蛋白质互助分析发现包括溶血磷脂酸受体1(LPAR1)、人腺苷酸环化酶5(ADCY5)等5个前列腺癌差异基因。筛选出651个差异甲基化位点,青绿色模块中有31个基因显著表达,同时也是差异表达基因。筛选出55个差异miRNA,参与这些miRNA的调节因子包括CRNDE、FENDRR、NEAT1和H19。差异转录因子的pivot分子包括KLF5、PGR、TWIST1、TWIST2。结论多个差异表达的蛋白编码基因及ncRNAs通过影响细胞迁移、调控转录因子及基因甲基化调控等作用,影响前列腺癌患病及进展,这可为了解前列腺癌机制及潜在治疗靶点提供一定理论基础。

Objective To explore the core genes and their regulatory networks related to the occurrence and progression of prostate cancer.Methods Gene expression data of 495 prostate cancer and 52 control samples,methylation microarray data of 498 prostate cancer and 50 control samples,miRNA expression profile data of 494 prostate cancer and 52 control samples were obtained from the Cancer Genome Atlas(TCGA)database from November 1,2018 to December 31,2018.From December 1,2020 to December 30,2020,prostate cancer-related genes on NCBI-gene and OMIM were integrated to construct the expression profile matrix of prostate cancer-causing genes,including coding protein genes,non-coding genes and methylated genes.Differential analysis,co-expression network analysis and pivot analysis were performed.ResultsA total of 1083 differentially expressed protein-coding genes were screened out,and 149 differentially expressed lncRNAs were found.Nine modules were found,and the most relevant modules for prostate cancer were brown and turquoise modules(P<0.001).The turquoise module could divide the samples into two clusters,and there was a statistically significant difference in the number of prostate cancer samples between the two clusters(163 cases vs.332 cases,P<0.05).Enrichment analysis showed that the turquoise module gene was related to biological processes such as cell adhesion and cell migration.These genes were involved in transforming growth factor-β(TCF-β)and peroxisome proliferator-activated receptor(PPAR)signaling pathways.It was correlated with the disease(P<0.05).Protein mutual analysis identified five differentially expressed genes,including lysophosphatidic acid receptor 1(LPAR1)and human adenylate cyclase 5(ADCY5).A total of 651 differentially methylated loci were screened,and 31 genes were significantly expressed in the cyan module,which were also differentially expressed genes.There were 55 differential mirnas,and the regulators involved in these mirnas included CRNDE,FENDRR,NEAT1 and H19.Pivot molecules of differential transcription factors include KLF5,PGR,TWIST1 and TWIST2.Conclusions Multiple differentially expressed protein-coding genes and ncRNAs affect the incidence and progression of prostate cancer by affecting cell migration,regulating transcription factors and gene methylation regulation,which provides a theoretical basis for understanding the mechanism and potential therapeutic targets of prostate cancer.