Wang Tao, Guo Tuanjie, Sun Juanjuan, Zang Xinyue, Dong Lei, Zhang Jian, Chen Siteng, Chen Guihua, Ma Sicong, Zhai Xinyu, Chu Chuanmin, Wang Chaofu, Wang Xiang, Xu Dongliang, Tan Mingyue
Department of Urology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Surgical Institute of Integrative Medicine, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Cell Biosci. 2025 Mar 27;15(1):40. doi: 10.1186/s13578-025-01379-w.
As the objective overall response rate to immune checkpoint inhibitors (ICIs) is less than 30% in late stage or metastatic bladder cancer (BLCA), elucidating the intrinsic mechanisms of immune evasion is of great importance for the discovery of predictive and prognostic biomarkers and the exploration of novel targets for intervention. Recent studies have shown that OBSCN and the cytoskeletal protein it encodes, obscurin, play an important role in tumour progression. However, no studies have reported the role of OBSCN in BLCA.
RNA sequencing and clinical data were downloaded from multiple public databases including The Cancer Genome Atlas and the Gene Expression Omnibus. Immunohistochemistry (IHC) was performed on tissue microarrays including 80 BLCA patients from Shuguang Hospital. Kaplan-Meier curves with log-rank test, univariate and multivariate COX regression were performed to evaluate the prognostic efficacy of OBSCN expression. In vitro experiments were conducted to determine the role of OBSCN deficiency in promoting BLCA progression. Pan-cancer tumour immune microenvironment (TIME) analysis was performed to explore the potential correlation between OBSCN deficiency and immune evasion.
Pan-cancers and single-cell sequencing analysis revealed that the expression level and proportion of OBSCN was significantly decreased in BLCA cells compared to normal urothelium. Survival curves showed that BLCA patients with low OBSCN expression had a worse prognosis, yet a better clinical response to PD-L1 ICIs. Gene set variation analysis and Gene set enrichment analysis revealed that epithelial-mesenchymal transition (EMT) and immune-related processes were significantly enriched in BLCA samples with low OBSCN expression. In vitro experiments identified that OBSCN-deficient BLCA cells enhanced invasion, migration and EMT. Pan-cancer analysis of TIME revealed that neoantigen, tumor mutation burden, CD8T cells and immune checkpoints were significantly negatively associated with OBSCN expression. IHC and Western blot assay identified that BLCA samples with low OBSCN expression had more CD8 T-cell infiltration and higher PD-L1 expression.
This study confirmed that BLCA patients with low OBSCN expression had a worse prognosis but a superior response to ICIs, providing a reference for individualised treatment of BLCA patients.
由于晚期或转移性膀胱癌（BLCA）对免疫检查点抑制剂（ICI）的客观总体缓解率低于30%，阐明免疫逃逸的内在机制对于发现预测性和预后生物标志物以及探索新的干预靶点至关重要。最近的研究表明，OBSCN及其编码的细胞骨架蛋白 obscurin 在肿瘤进展中起重要作用。然而，尚无研究报道 OBSCN 在 BLCA 中的作用。
从多个公共数据库（包括癌症基因组图谱和基因表达综合数据库）下载 RNA 测序和临床数据。对包括来自曙光医院的80例 BLCA 患者的组织芯片进行免疫组织化学（IHC）检测。采用 Kaplan-Meier 曲线结合对数秩检验、单因素和多因素 COX 回归分析来评估 OBSCN 表达的预后效果。进行体外实验以确定 OBSCN 缺陷在促进 BLCA 进展中的作用。进行泛癌肿瘤免疫微环境（TIME）分析以探索 OBSCN 缺陷与免疫逃逸之间的潜在相关性。
泛癌和单细胞测序分析显示，与正常尿路上皮相比，BLCA 细胞中 OBSCN 的表达水平和比例显著降低。生存曲线显示，OBSCN 表达低的 BLCA 患者预后较差，但对 PD-L1 ICI 的临床反应较好。基因集变异分析和基因集富集分析显示，在 OBSCN 表达低的 BLCA 样本中，上皮-间质转化（EMT）和免疫相关过程显著富集。体外实验表明，OBSCN 缺陷的 BLCA 细胞增强了侵袭、迁移和 EMT。TIME 的泛癌分析显示，新抗原、肿瘤突变负荷、CD8 T 细胞和免疫检查点与 OBSCN 表达显著负相关。IHC 和蛋白质印迹分析表明，OBSCN 表达低的 BLCA 样本有更多的 CD8 T 细胞浸润和更高的 PD-L1 表达。
本研究证实，OBSCN 表达低的 BLCA 患者预后较差，但对 ICI 反应较好，为 BLCA 患者的个体化治疗提供了参考。
