肿瘤细胞治疗研究
英文原题：Identification of novel protein markers and therapeutic targets for common urological cancers by integrating large-scale human plasma proteome with the genome.
本研究突出了几种对BC和PC风险具有预测价值的蛋白质，并支持其在生物标志物发现和药物开发中的应用。
考虑到循环蛋白质组是候选生物标志物和治疗靶点的主要来源，我们开展了一项大规模孟德尔随机化（MR）研究，以识别可能参与常见泌尿系统癌症（UCs）发病机制和治疗的血浆蛋白，包括膀胱癌（BC）、前列腺癌（PC）、肾细胞癌（RCC）和睾丸癌（TC）。顺式蛋白定量性状位点（cis-pQTLs）来源于两项大规模血浆蛋白质组全基因组关联研究（GWAS）。UCs的GWAS数据来自FinnGen和pan-UKBB meta分析、FinnGen和UK Biobank。进行了共定位分析和基于汇总数据的MR（SMR）以评估关联的稳健性。进一步评估包括Bulk RNA-seq差异表达和单细胞类型表达分析、蛋白-蛋白相互作用以及可成药性评价。对于BC，我们识别了四种蛋白标志物：一种与风险增加相关（PSCA），三种与风险降低相关（GSTM1、GSTM3、GSTM4），这些蛋白主要表达于膀胱肿瘤中的周细胞、尿路上皮细胞和NK细胞。关于PC，我们发现了15种蛋白标志物：七种与风险增加相关（AGER、ALAD、CHMP2B、PEX14、ZG16B、PPP1R14A、SERPINA3），八种与风险降低相关（BTN2A1、CEACAM21、DNAJB9、MSMB、PYGL、HLA-E、SOD2、TOR1AIP1），富集于前列腺肿瘤中的上皮细胞、单核细胞/巨噬细胞。来自MR和共定位分析的最强证据支持GSTM4（BC）、SOD2和CHMP2B（PC）作为因果标志物。值得注意的是，七种已识别的蛋白此前已被用于其他癌症和免疫疾病的药物靶向，表明它们在UCs中具有潜在的治疗相关性。本研究突出了几种对BC和PC风险具有预测价值的蛋白，并支持其在生物标志物发现和药物开发中的应用。
Considering that the circulating proteome represents a primary source of candidate biomarkers and therapeutic targets, we conducted a large-scale Mendelian randomization (MR) study to identify plasma proteins potentially involved in the pathogenesis and treatment of common urological cancers (UCs), including bladder cancer (BC), prostate cancer (PC), renal cell carcinoma (RCC), and testicular cancer (TC). Cis-protein quantitative trait loci (cis-pQTLs) were derived from two large-scale genome-wide association studies (GWASs) of plasma proteomes. GWAS for UCs were obtained from FinnGen and pan-UKBB meta-analysis, FinnGen and UK Biobank. Colocalization analysis and summary data-based MR (SMR) were performed to evaluate the robustness of the associations. Further evaluations involved Bulk RNA-seq differential expression and single cell-type expression analysis, protein–protein interaction, and druggability evaluation. For BC, we identified four protein markers: one associated with increased risk (PSCA) and three with decreased risk (GSTM1, GSTM3, GSTM4), which are mainly expressed in pericyte, urothelial, and NK cells in bladder tumors. Regarding PC, we found 15 protein markers: seven linked to increased risk (AGER, ALAD, CHMP2B, PEX14, ZG16B, PPP1R14A, SERPINA3) and eight to decreased risk (BTN2A1, CEACAM21, DNAJB9, MSMB, PYGL, HLA-E, SOD2, TOR1AIP1), enriched in epithelial cells, monocytes/macrophages in prostate tumors. The strongest evidence from MR and colocalization analyses supported GSTM4 (BC), SOD2 and CHMP2B (PC) as causal markers. Notably, seven identified proteins have been previously targeted by drugs for other cancers and immune disorders, indicating their potential therapeutic relevance in UCs. This study highlights several proteins with predictive value for BC and PC risk and supports their utility in biomarker discovery and drug development.
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