Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA.
Department of Biostatistics, Florida International University, Miami, FL 33199, USA.
Int J Mol Sci. 2023 Feb 6;24(4):3191. doi: 10.3390/ijms24043191.
Prostate cancer (PCa) is one of the most frequently diagnosed cancers among men in the world. Its prevention has been limited because of an incomplete understanding of how environmental exposures to chemicals contribute to the molecular pathogenesis of aggressive PCa. Environmental exposures to endocrine-disrupting chemicals (EDCs) may mimic hormones involved in PCa development. This research aims to identify EDCs associated with PCa hub genes and/or transcription factors (TF) of these hub genes in addition to their protein-protein interaction (PPI) network. We are expanding upon the scope of our previous work, using six PCa microarray datasets, namely, GSE46602, GSE38241, GSE69223, GSE32571, GSE55945, and GSE26126, from the NCBI/GEO, to select differentially expressed genes based on |log2FC| (fold change) ≥ 1 and an adjusted -value < 0.05. An integrated bioinformatics analysis was used for enrichment analysis (using DAVID.6.8, GO, KEGG, STRING, MCODE, CytoHubba, and GeneMANIA). Next, we validated the association of these PCa hub genes in RNA-seq PCa cases and controls from TCGA. The influence of environmental chemical exposures, including EDCs, was extrapolated using the chemical toxicogenomic database (CTD). A total of 369 overlapping DEGs were identified associated with biological processes, such as cancer pathways, cell division, response to estradiol, peptide hormone processing, and the p53 signaling pathway. Enrichment analysis revealed five up-regulated (NCAPG, MKI67, TPX2, CCNA2, CCNB1) and seven down-regulated (CDK1, CCNB2, AURKA, UBE2C, BUB1B, CENPF, RRM2) hub gene expressions. Expression levels of these hub genes were significant in PCa tissues with high Gleason scores ≥ 7. These identified hub genes influenced disease-free survival and overall survival of patients 60-80 years of age. The CTD studies showed 17 recognized EDCs that affect TFs (NFY, CETS1P54, OLF1, SRF, COMP1) that are known to bind to our PCa hub genes, namely, NCAPG, MKI67, CCNA2, CDK1, UBE2C, and CENPF. These validated differentially expressed hub genes can be potentially developed as molecular biomarkers with a systems perspective for risk assessment of a wide-ranging list of EDCs that may play overlapping and important role(s) in the prognosis of aggressive PCa.
前列腺癌（PCa）是全球男性中最常见的癌症之一。由于对环境化学暴露如何导致侵袭性 PCa 的分子发病机制了解不足，其预防一直受到限制。环境内分泌干扰化学物质（EDCs）的暴露可能模拟与 PCa 发展有关的激素。本研究旨在确定与 PCa 枢纽基因相关的 EDCs 以及这些枢纽基因的转录因子（TF），以及它们的蛋白质-蛋白质相互作用（PPI）网络。我们正在扩展之前工作的范围，使用来自 NCBI/GEO 的六个 PCa 微阵列数据集，即 GSE46602、GSE38241、GSE69223、GSE32571、GSE55945 和 GSE26126，根据 |log2FC|（倍数变化）≥1 和调整后的 - 值<0.05 选择差异表达基因。使用集成的生物信息学分析进行富集分析（使用 DAVID.6.8、GO、KEGG、STRING、MCODE、CytoHubba 和 GeneMANIA）。接下来，我们在 TCGA 的 RNA-seq PCa 病例和对照中验证了这些 PCa 枢纽基因的相关性。使用化学毒理基因组数据库（CTD）推断环境化学暴露物（包括 EDCs）的影响。确定了 369 个与生物过程相关的重叠 DEG，例如癌症途径、细胞分裂、对雌二醇的反应、肽激素处理和 p53 信号通路。富集分析显示，有 5 个上调（NCAPG、MKI67、TPX2、CCNA2、CCNB1）和 7 个下调（CDK1、CCNB2、AURKA、UBE2C、BUB1B、CENPF、RRM2）枢纽基因表达。这些枢纽基因在高 Gleason 评分≥7 的 PCa 组织中的表达水平具有显著性。这些鉴定的枢纽基因影响 60-80 岁患者的无病生存率和总生存率。CTD 研究表明，有 17 种公认的 EDCs 会影响已知与我们的 PCa 枢纽基因（NCAPG、MKI67、CCNA2、CDK1、UBE2C 和 CENPF）结合的 TF（NFY、CETS1P54、OLF1、SRF、COMP1）。这些经过验证的差异表达枢纽基因可以作为分子生物标志物进行潜在开发，从系统角度评估广泛的 EDC 清单，这些 EDC 可能在侵袭性 PCa 的预后中发挥重叠和重要作用。
