Tao Junyue, Chen Yiding, Bian Xiaokang, Cai Tingting, Song Changhao, Liang Chaozhao, Hao Zongyao, Meng Jialing, Ge Qintao, Zhou Jun
Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Institute of Urology, Anhui Medical University, Hefei, China.
Front Immunol. 2025 Jun 11;16:1618487. doi: 10.3389/fimmu.2025.1618487. eCollection 2025.
Recent studies have underscored the potential involvement of cathepsin Z (CTSZ) in modulating the progression of diverse tumor types. Nevertheless, its specific role in prostate cancer (PCa) remains insufficiently understood. This study aimed to investigate the expression profile of CTSZ in PCa and evaluate its prognostic significance.
Three independent cohorts, including TCGA-PRAD, MSKCC, and a real-world AHMU-PC cohort were enrolled in this study. Multidimensional strategies consist of spatial transcriptome analysis, differential expression analysis, survival analysis, and correlation with clinicopathological features were performed. Immunohistochemical staining and multiplex immunofluorescence staining were performed to evaluate the expression and spatial distribution of CTSZ and immune-related markers in PCa tissues. Functional studies were conducted through a series of experiments, including CCK-8 assay, colony formation, wound healing, and Transwell migration assays. ssGSEA and CIBERSORT algorithms immune infiltration evaluation, and GISTIC2.0 and MutSigCV for tumor mutation burden. Gene Set Enrichment Analysis was performed to identify potential signaling pathways involved.
CTSZ is highly expressed in PCa tissues and is associated with higher Gleason scores, advanced T/N staging, and poor prognosis. Survival analyses across multiple cohorts indicate that high CTSZ expression predicts shorter progression-free survival and overall survival. experiments showed that CTSZ knockdown suppresses PCa cell proliferation, invasion, migration, and colony formation. Immune profiling revealed that high-CTSZ tumors exhibit an immune-enriched microenvironment, characterized by increased infiltration of regulatory T cells and M2 macrophages, suggesting an immunosuppressive state. Notably, despite this phenotype, PD-1 and PD-L1 levels were also elevated in high-CTSZ tumors, indicating a potential role in immune checkpoint regulation. Additionally, high CTSZ expression was correlated with increased tumor mutation burden, particularly enriched for and mutations. GSEA identified CAM, VEGF, and STAT signaling pathways as potential mechanisms through which CTSZ promotes tumor progression, highlighting its potential as both a prognostic biomarker and therapeutic target in PCa.
Our study highlights CTSZ as a potential prognostic and therapeutic biomarker in PCa, demonstrating that its overexpression is associated with immune cell infiltration, immune checkpoint molecule expression (such as PD-1 and PD-L1), tumor mutation burden, and key oncogenic pathways. These findings suggest that CTSZ may serve not only as a predictor of patient prognosis but also as a promising indicator for immunotherapy response and personalized treatment strategies in PCa.
近期研究强调了组织蛋白酶Z（CTSZ）在调节多种肿瘤类型进展中的潜在作用。然而，其在前列腺癌（PCa）中的具体作用仍未得到充分了解。本研究旨在调查CTSZ在PCa中的表达谱并评估其预后意义。
本研究纳入了三个独立队列，包括TCGA-PRAD、MSKCC和一个真实世界的AHMU-PC队列。采用了包括空间转录组分析、差异表达分析、生存分析以及与临床病理特征相关性分析在内的多维度策略。进行了免疫组织化学染色和多重免疫荧光染色，以评估CTSZ和免疫相关标志物在PCa组织中的表达及空间分布。通过一系列实验进行功能研究，包括CCK-8检测、集落形成、伤口愈合和Transwell迁移实验。采用ssGSEA和CIBERSORT算法评估免疫浸润，并使用GISTIC2.0和MutSigCV评估肿瘤突变负荷。进行基因集富集分析以确定潜在的相关信号通路。
CTSZ在PCa组织中高表达，且与更高的Gleason评分、晚期T/N分期及不良预后相关。多个队列的生存分析表明，CTSZ高表达预示着无进展生存期和总生存期较短。实验表明，敲低CTSZ可抑制PCa细胞的增殖、侵袭、迁移和集落形成。免疫分析显示，高CTSZ表达的肿瘤呈现免疫富集的微环境，其特征为调节性T细胞和M2巨噬细胞浸润增加，提示处于免疫抑制状态。值得注意的是，尽管有此表型，高CTSZ表达的肿瘤中PD-1和PD-L1水平也升高，表明其在免疫检查点调节中可能发挥作用。此外，CTSZ高表达与肿瘤突变负荷增加相关，尤其富集于[具体突变类型1]和[具体突变类型2]突变。基因集富集分析确定CAM、VEGF和STAT信号通路是CTSZ促进肿瘤进展的潜在机制，突出了其作为PCa预后生物标志物和治疗靶点的潜力。
我们的研究强调CTSZ是PCa中一种潜在的预后和治疗生物标志物，表明其过表达与免疫细胞浸润、免疫检查点分子表达（如PD-1和PD-L1）、肿瘤突变负荷及关键致癌通路相关。这些发现表明，CTSZ不仅可作为患者预后的预测指标，还可能是PCa免疫治疗反应和个性化治疗策略的有前景指标。
