Zuo Jieming, Chen Junhao, Tan Zhiyong, Wen Lingxiang, Zhao Junxian, Fu Yuanzhi, Wang Haifeng, Fu Shi, Wang Jiansong
Yunnan Institute of Urology, The Second Affiliated Hospital of Kunming Medical University, Kunming 650101, China.
Kunming Medical University, Kunming City, Yunnan Province, China.
J Cancer. 2025 Jul 11;16(10):3163-3179. doi: 10.7150/jca.116402. eCollection 2025.
Bladder cancer is characterized by a high recurrence rate and aggressive behavior, with frequent emergence of chemoresistance. Current treatments such as surgery, chemotherapy, and immunotherapy have limited efficacy, underscoring the urgent need for effective early diagnostic biomarkers and novel targeted therapies. In this study, we integrated plasma proteomic data from the UK Biobank Pharma Proteomics Project (UKB-PPP) and the Icelandic deCODE study with genome-wide association study (GWAS) data. We employed two-sample Mendelian randomization (MR), Bayesian colocalization analysis, and SMR/HEIDI tests to systematically identify potential plasma protein targets associated with bladder cancer risk. A total of 199 plasma proteins were found to be significantly associated with bladder cancer risk, among which five proteins (SLURP1, LY6D, WFDC1, NOV, and GSTM3) emerged as core candidate targets. Further validation showed that NOV and GSTM3 demonstrated robust causal associations with bladder cancer across multiple analytical methods, and molecular docking analysis revealed that these two proteins can bind to estrogen/progestin hormone-regulating drugs. Our study identified multiple plasma proteins with causal links to bladder cancer and revealed their potential roles in tumor immune evasion, antioxidant defenses, and tumor metabolism. These findings provide new insights into bladder cancer biology and offer potential targets for precision therapy and drug repositioning.
膀胱癌的特点是复发率高且行为侵袭性强，常出现化疗耐药。目前的治疗方法，如手术、化疗和免疫疗法，疗效有限，这凸显了对有效早期诊断生物标志物和新型靶向治疗的迫切需求。在本研究中，我们将来自英国生物银行药物蛋白质组学项目（UKB-PPP）和冰岛deCODE研究的血浆蛋白质组数据与全基因组关联研究（GWAS）数据进行了整合。我们采用两样本孟德尔随机化（MR）、贝叶斯共定位分析和SMR/HEIDI检验，系统地识别与膀胱癌风险相关的潜在血浆蛋白靶点。共发现199种血浆蛋白与膀胱癌风险显著相关，其中5种蛋白（SLURP1、LY6D、WFDC1、NOV和GSTM3）成为核心候选靶点。进一步验证表明，NOV和GSTM3在多种分析方法中均显示出与膀胱癌的强大因果关联，分子对接分析表明这两种蛋白可与雌激素/孕激素调节药物结合。我们的研究确定了多种与膀胱癌存在因果关系的血浆蛋白，并揭示了它们在肿瘤免疫逃逸、抗氧化防御和肿瘤代谢中的潜在作用。这些发现为膀胱癌生物学提供了新的见解，并为精准治疗和药物重新定位提供了潜在靶点。
