Alwadi Diaaidden, Felty Quentin, Doke Mayur, Roy Deodutta, Yoo Changwon, Deoraj Alok
Department of Environmental Health Sciences, Florida International University, Miami, FL 33199, USA.
Diabetes Research Institute, University of Miami, Miami, FL 33136, USA.
Int J Mol Sci. 2025 Jun 6;26(12):5463. doi: 10.3390/ijms26125463.
This study analyzes publicly available RNA-seq data to comprehensively include the complex heterogeneity of prostate cancer (PCa) etiology. It combines prostate and prostate cancer (PCa) cell lines, representing primary PCa cells, Gleason scores, ages, and PCa of different racial origins. Additionally, some cell lines were exposed to endocrine-disrupting chemicals (EDCs). The research aims to identify hub genes and transcription factors (TFs) of the prostate carcinogenesis pathway as molecular targets for clinical investigations to elucidate EDC-induced aggressiveness and to develop potential biomarkers for their exposure risk assessments. PCa cells rely on androgen receptor (AR)-mediated signaling to survive, develop, and function. Fifteen various RNA-seq datasets were normalized for distribution, and the significance (-value < 0.05) threshold of differentially expressed genes (DEGs) was set based on |log2FC| ≥ 2 change. Through integrated bioinformatics, we applied cBioPortal, UCSC-Xena, TIMER2.0, and TRRUST platforms, among others, to associate hub genes and their TFs based on their biologically meaningful roles in aggressive prostate carcinogenesis. Among all RNA-Seq datasets, we found 75 overlapping DEGs, with BUB1B (32%) and CCNB1 (29%) genes exhibiting the highest degree of mutation, amplification, and deletion. EDC-associated CCNB1, BUB1B, and CCNA2 in PCa cells exposed to EDCs were consistently shown to be associated with high Gleason scores (≥4 + 3) and in the >60 age group of patients. Selected TFs (E2F4, MYC, and YBX1) were also significantly associated with DEGs (NCAPG, MKI67, CCNA2, CCNB1, CDK1, CCNB2, AURKA, UBE2C, BUB1B) and influenced the overall survival (-value < 0.05) of PCa cases. This is one of the first comprehensive studies combining 15 publicly available RNA-seq datasets to demonstrate the association of EDC-associated hub genes and their TFs aligning with the aggressive carcinogenic pathways in the higher age group (>60 years) of patients. The findings highlight the potential of these hub genes as candidates for further studies to develop molecular biomarkers for assessing the EDC-related PCa risk, diagnosing PCa aggressiveness, and identifying therapeutic targets.
本研究分析公开可用的RNA测序数据，以全面涵盖前列腺癌（PCa）病因的复杂异质性。它结合了前列腺和前列腺癌细胞系，代表原发性PCa细胞、 Gleason评分、年龄以及不同种族来源的PCa。此外，一些细胞系暴露于内分泌干扰化学物质（EDC）。该研究旨在确定前列腺癌发生途径的核心基因和转录因子（TF），作为临床研究的分子靶点，以阐明EDC诱导的侵袭性，并开发用于评估其暴露风险的潜在生物标志物。PCa细胞依赖雄激素受体（AR）介导的信号来存活、发育和发挥功能。对15个不同的RNA测序数据集进行了分布标准化，并根据|log2FC|≥2的变化设定了差异表达基因（DEG）的显著性（-值<0.05）阈值。通过综合生物信息学，我们应用了cBioPortal、UCSC-Xena、TIMER2.0和TRRUST等平台，根据其在侵袭性前列腺癌发生中的生物学意义，将核心基因及其TF关联起来。在所有RNA测序数据集中，我们发现了75个重叠的DEG，其中BUB1B（32%）和CCNB1（29%）基因表现出最高程度的突变、扩增和缺失。在暴露于EDC的PCa细胞中，与EDC相关的CCNB1、BUB1B和CCNA2一直显示与高Gleason评分（≥4+3）以及年龄>60岁的患者组相关。选定的TF（E2F4、MYC和YBX1）也与DEG（NCAPG、MKI67、CCNA2、CCNB1、CDK1、CCNB2、AURKA、UBE2C、BUB1B）显著相关，并影响PCa病例的总生存期（-值<0.05）。这是首批综合研究之一，结合了15个公开可用的RNA测序数据集，以证明与EDC相关的核心基因及其TF与年龄较大（>60岁）患者组中侵袭性致癌途径的关联。这些发现突出了这些核心基因作为进一步研究候选者的潜力，以开发用于评估与EDC相关的PCa风险、诊断PCa侵袭性和识别治疗靶点的分子生物标志物。
