Liu Jia-Hao, Du Yuan-Zhuo, Liu Fang, Yang Lin, Liu Xiao-Qiang, Fu Bin, Yang Xiao-Rong
The First Affiliated Hospital of Nanchang University Nanchang, Jiangxi, China.
Am J Cancer Res. 2025 Mar 15;15(3):1096-1108. doi: 10.62347/UBEJ3345. eCollection 2025.
The incidence of bladder cancer (BCa) is increasing worldwide and the development of drug targets for BCa is necessary. We conducted a proteome-wide association study (PWAS) mainly using mendelian randomization (MR) to explore the causal proteins associated with BCa. Protein quantitative trait locis (pQTLs) were derived from two large proteome genome-wide association studies. After validation by multiple sensitivity analysis and two replication analyses, we identified five plasma proteins showed significant causal associations with BCa. Our study indicated that GSTM4 (OR = 0.81 (0.74-0.89), = 5.14 × 10, PPH4 = 0.89) emerged as the most reliable target. Besides, PSCA, LY6D, SLURP1 and GSTM1 also showed clear causal association but only failed in colocalization. We also performed several downstream analyses. Protein-protein interactions analysis found these causal targets came from glutathione S-transferase family or lymphocyte antigen-6 family. Phenome-wide MR analysis revealed PSCA may lead to peptic ulcer and local infections of skin and subcutaneous tissue. We then employed single-cell analysis, protein-protein interactions, and druggability evaluation. Phenome-wide MR analysis was to assess the possible side effects of these drug targets. Finally, the reliability of GSTM4 in BCa was confirmed via colony formation assay.
全球范围内膀胱癌（BCa）的发病率正在上升，因此开发针对BCa的药物靶点很有必要。我们主要利用孟德尔随机化（MR）进行了一项全蛋白质组关联研究（PWAS），以探索与BCa相关的因果蛋白。蛋白质定量性状位点（pQTLs）来自两项大型蛋白质组全基因组关联研究。经过多次敏感性分析和两次重复分析验证后，我们确定了五种血浆蛋白与BCa存在显著的因果关联。我们的研究表明，谷胱甘肽S-转移酶M4（GSTM4）（比值比=0.81（0.74-0.89）， = 5.14 × 10，PPH4 = 0.89）成为最可靠的靶点。此外，前列腺干细胞抗原（PSCA）、淋巴细胞抗原6D（LY6D）、分泌型跨膜蛋白1（SLURP1）和谷胱甘肽S-转移酶M1（GSTM1）也显示出明显的因果关联，但仅在共定位分析中未通过验证。我们还进行了几项下游分析。蛋白质-蛋白质相互作用分析发现，这些因果靶点来自谷胱甘肽S-转移酶家族或淋巴细胞抗原6家族。全表型组MR分析显示，PSCA可能导致消化性溃疡以及皮肤和皮下组织的局部感染。然后，我们进行了单细胞分析、蛋白质-蛋白质相互作用分析和药物可及性评估。全表型组MR分析旨在评估这些药物靶点可能产生的副作用。最后，通过集落形成试验证实了GSTM4在BCa中的可靠性。
