Li Wei, Wei Xi, Yu Ying, Tian Yuan, Yu Qi, Qiao Jun, Tao Yuewei, Li Yanfeng, Li Tao
Department of Urology, the Affiliated Hospital of Guizhou Medical University, Guiyang, China.
Zhejiang Provincial People's Hospital Bijie Hospital, Bijie, China.
Front Immunol. 2025 Jun 18;16:1582992. doi: 10.3389/fimmu.2025.1582992. eCollection 2025.
Prostate cancer (PCa) is the most common male malignancy and significantly impairs patient's survival. Matrix metalloproteinases (MMPs) play a crucial role in tumor progression, yet the comprehensive role of MMPs in PCa remains unclear.
Data from UCSC and GEO databases were firstly analyzed to evaluate expression characteristics, prognostic value, immune-cell infiltration, tumor-mutation burden (TMB), microsatellite-instability (MSI), immunotherapy sensitivity, and drug sensitivity in PCa. COX-regression analysis was utilized to identify MMPs that affected (Disease-free survival) DFS. Various cellular functional experiments and conditional medium cultivation system were utilized to verify the effect of MMP11 on PCa cells. Subsequently, single-cell transcriptome and spatial-transcriptome data was analyzed to explore the regulatory effect of MMP11 on microenvironment.
Most MMPs exhibit differential expression between tumor and normal tissues, with specific MMPs correlating with pathological features of PCa. Among 24 MMPs analyzed, MMP11 was uniquely associated with shorter DFS. High MMP11 expression correlated with increased infiltration of regulatory Tregs and M2 macrophages, elevated immune checkpoint molecule expression, higher TMB, MSI, and enhanced immunotherapy sensitivity. MMP11 suppression inhibited PCa cell proliferation, migration, invasion, and epithelial-mesenchymal transition.MMP11 was predominantly expressed in fibroblasts and linked to the establishment of an immunosuppressive tumor microenvironment. Targeting MMP11 in cancer-associated fibroblasts reversed their pro-tumorigenic effects on PCa progression. Finally, MMP11 is broadly upregulated across malignancies and associated with poor prognosis in multiple cancer types.
This study comprehensively explored the role of MMPs in PCa. Noteworthy, we further proved that MMP11 significantly promoted PCa probably through reprogramming of tumor microenvironment, which might provide a promising-target for PCa treatment.
前列腺癌（PCa）是最常见的男性恶性肿瘤，严重影响患者的生存。基质金属蛋白酶（MMPs）在肿瘤进展中起关键作用，但MMPs在PCa中的综合作用仍不清楚。
首先分析来自UCSC和GEO数据库的数据，以评估PCa中的表达特征、预后价值、免疫细胞浸润、肿瘤突变负担（TMB）、微卫星不稳定性（MSI）、免疫治疗敏感性和药物敏感性。利用COX回归分析来确定影响无病生存期（DFS）的MMPs。采用各种细胞功能实验和条件培养基培养系统来验证MMP11对PCa细胞的作用。随后，分析单细胞转录组和空间转录组数据，以探索MMP11对微环境的调节作用。
大多数MMPs在肿瘤组织和正常组织之间表现出差异表达，特定的MMPs与PCa的病理特征相关。在分析的24种MMPs中，MMP11与较短的DFS唯一相关。高MMP11表达与调节性Tregs和M2巨噬细胞浸润增加、免疫检查点分子表达升高、更高的TMB、MSI以及增强的免疫治疗敏感性相关。抑制MMP11可抑制PCa细胞的增殖、迁移、侵袭和上皮-间质转化。MMP11主要在成纤维细胞中表达，并与免疫抑制性肿瘤微环境的形成有关。靶向癌症相关成纤维细胞中的MMP11可逆转其对PCa进展的促肿瘤作用。最后，MMP11在多种恶性肿瘤中广泛上调，并与多种癌症类型的不良预后相关。
本研究全面探讨了MMPs在PCa中的作用。值得注意的是，我们进一步证明MMP11可能通过重编程肿瘤微环境显著促进PCa，这可能为PCa治疗提供一个有前景的靶点。
