Shan Weimin, Guan Bo, Ma Weiwei, Fan Runzhe, Cui Di, Hao Zongyao
Department of Urology, Fuyang People's Hospital of Anhui Medical University, Fuyang, China.
Fuyang Medical College, Fuyang Normal University, Fuyang, China.
Sci Rep. 2025 Jul 28;15(1):27467. doi: 10.1038/s41598-025-10624-8.
Prostate cancer is a heterogeneous malignancy with a complex tumor microenvironment (TME) composed of various cellular components, including fibroblasts. These fibroblasts, particularly cancer-associated fibroblasts (CAFs), are crucial in shaping the TME and influencing cancer progression. Catechol-O-methyltransferase (COMT), a key enzyme involved in the metabolism of catecholamines and oxidative stress regulation, has recently been implicated in cancer biology. This study aims to explore the molecular landscape of fibroblasts in prostate cancer and evaluate the prognostic significance of COMT expression in this context. We performed an integrated single-cell RNA sequencing (scRNA-seq) analysis on prostate cancer samples from Gene Expression Omnibus (GEO) databases. Fibroblast subpopulations were identified through clustering, and functional gene signatures for each subgroup were characterized. Prognostic analysis was carried out using univariate and multivariate Cox regression to identify genes associated with patient survival, culminating in a risk score model using data from the Cancer Genome Atlas (TCGA). Additionally, immunofluorescence assays were used to validate COMT expression in tumor-derived fibroblasts. Our single-cell sequencing analysis revealed three distinct fibroblast subpopulations, each with unique gene expression profiles linked to extracellular matrix remodeling, immune modulation, and cellular stress responses. COMT was identified as a key gene in tumor-derived fibroblasts, with its expression significantly higher in tumor samples compared to normal tissues. The risk score model, based on COMT and other fibroblast-associated genes (QSOX1, TAX1BP3, CCDC66, MTCH1, ARL2BP), successfully stratified patients into high-risk and low-risk groups, with higher risk scores correlating with poorer survival outcomes. Immunostaining confirmed the overexpression of COMT in tumor-derived fibroblasts, consistent with bioinformatics analysis. This study underscores the significant role of fibroblasts, particularly CAFs, in prostate cancer progression. Our findings highlight COMT as a critical regulator of the tumor microenvironment and a promising prognostic marker. The integration of single-cell RNA-seq with clinical data offers new insights into fibroblast heterogeneity and the potential for COMT as a therapeutic target in prostate cancer. Further research is needed to validate these findings and explore the mechanistic role of COMT in prostate cancer progression and therapeutic resistance.
前列腺癌是一种异质性恶性肿瘤，其肿瘤微环境（TME）复杂，由包括成纤维细胞在内的多种细胞成分组成。这些成纤维细胞，尤其是癌症相关成纤维细胞（CAFs），在塑造TME和影响癌症进展方面至关重要。儿茶酚-O-甲基转移酶（COMT）是一种参与儿茶酚胺代谢和氧化应激调节的关键酶，最近已被证明与癌症生物学有关。本研究旨在探索前列腺癌中成纤维细胞的分子图谱，并评估在这种情况下COMT表达的预后意义。我们对来自基因表达综合数据库（GEO）的前列腺癌样本进行了综合单细胞RNA测序（scRNA-seq）分析。通过聚类识别成纤维细胞亚群，并对每个亚组的功能基因特征进行表征。使用单变量和多变量Cox回归进行预后分析，以识别与患者生存相关的基因，最终使用来自癌症基因组图谱（TCGA）的数据建立风险评分模型。此外，免疫荧光分析用于验证肿瘤来源成纤维细胞中COMT的表达。我们的单细胞测序分析揭示了三个不同的成纤维细胞亚群，每个亚群都有与细胞外基质重塑、免疫调节和细胞应激反应相关的独特基因表达谱。COMT被确定为肿瘤来源成纤维细胞中的关键基因，其在肿瘤样本中的表达明显高于正常组织。基于COMT和其他成纤维细胞相关基因（QSOX1、TAX1BP3、CCDC66、MTCH1、ARL2BP）的风险评分模型成功地将患者分为高风险和低风险组，风险评分越高，生存结果越差。免疫染色证实了COMT在肿瘤来源成纤维细胞中的过表达，与生物信息学分析一致。本研究强调了成纤维细胞，尤其是CAFs，在前列腺癌进展中的重要作用。我们的研究结果突出了COMT作为肿瘤微环境的关键调节因子和有前景的预后标志物。单细胞RNA-seq与临床数据的整合为成纤维细胞异质性以及COMT作为前列腺癌治疗靶点的潜力提供了新的见解。需要进一步的研究来验证这些发现，并探索COMT在前列腺癌进展和治疗耐药中的机制作用。
