Chen Yu-Sen, Yang Wei-Bang, Li Yi-Hu, Xu Jin-Yang, Wei Yu-Xuan, Huang Si-Min, Jiang Xiao-Feng, Li Jian-Hui
Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Guangzhou Medical University, 250 Changgang East Rd, Guangzhou, 510220, Guangdong, China.
J Gastrointest Cancer. 2025 Apr 17;56(1):100. doi: 10.1007/s12029-025-01226-8.
The proteome serves as a key source for the discovery of therapeutic targets. This study utilized proteome-wide Mendelian randomization (MR) to identify protein biomarkers potentially associated with intrahepatic cholangiocarcinoma (ICC).
We derived protein quantitative trait loci (pQTLs) from the deCODE plasma proteome GWAS and genetic ICC associations from a European meta-analysis. Proteome-wide MR identified candidate proteins linked to ICC risk. Expression of MR-identified biomarkers in the plasma of ICC patients was detected by ELISA. ScRNA-seq analysis detected the specific cell type with enrichment expression. Prognostic and diagnostic evaluations in ICC of these proteins were performed using samples derived from TCGA and GTEx databases.
MR analysis genetically predicted 5 proteins were associated with ICC risk (STX12, A2M, CD163, CXADR and FOXJ2). The results of the MR analysis for the five identified targets were consistent with the measured plasma concentrations of these targets in ICC patients and healthy volunteers. The differential RNA-seq analysis between tumor and adjacent normal tissues showed that STX12 was expressed at higher levels in tumor tissues, while A2M, CXADR, CD163, and FOXJ2 were expressed at higher levels in adjacent normal tissues. ScRNA-seq analysis revealed that these protein-coding genes are mainly expressed in TAMs, TEC, HPC-like cells and malignant cells in ICC tumor tissue. Prognosis analysis showed higher CXADR expression correlated with longer OS in CHOL (P = 0.041). The AUC for A2M, CD163, CXADR, FOXJ2, and STX12 were 0.975, 0.705, 0.917, 0.997, and 0.956, respectively.
This study represents the first Proteome-MR analysis of ICC, revealing its complex genetic architecture and identifying five novel blood proteins with potential causal links to the disease. Through proteome-MR analysis, scRNA-seq analysis, and diagnostic-prognostic evaluation using TCGA and GTEx databases, these proteins were assessed as promising therapeutic and diagnostic targets. The findings provide a theoretical foundation for future ICC treatment strategies.
蛋白质组是发现治疗靶点的关键来源。本研究利用全蛋白质组孟德尔随机化（MR）来鉴定可能与肝内胆管癌（ICC）相关的蛋白质生物标志物。
我们从deCODE血浆蛋白质组全基因组关联研究（GWAS）中推导蛋白质定量性状位点（pQTL），并从一项欧洲荟萃分析中获取遗传性ICC关联数据。全蛋白质组MR鉴定出与ICC风险相关的候选蛋白质。通过酶联免疫吸附测定（ELISA）检测MR鉴定的生物标志物在ICC患者血浆中的表达。单细胞RNA测序（scRNA-seq）分析检测到富集表达的特定细胞类型。使用来自癌症基因组图谱（TCGA）和基因型组织表达（GTEx）数据库的样本对这些蛋白质在ICC中进行预后和诊断评估。
MR分析通过基因预测5种蛋白质与ICC风险相关（ syntaxin 12，α-2巨球蛋白，CD163，柯萨奇病毒和腺病毒受体，叉头框J2）。对这五个鉴定靶点的MR分析结果与ICC患者和健康志愿者中这些靶点的血浆测量浓度一致。肿瘤组织与癌旁正常组织之间的差异RNA测序分析表明， syntaxin 12在肿瘤组织中表达较高，而α-2巨球蛋白、柯萨奇病毒和腺病毒受体、CD163和叉头框J2在癌旁正常组织中表达较高。scRNA-seq分析显示，这些蛋白质编码基因主要在ICC肿瘤组织中的肿瘤相关巨噬细胞、肿瘤内皮细胞、肝祖细胞样细胞和恶性细胞中表达。预后分析显示，在胆管癌（CHOL）中，柯萨奇病毒和腺病毒受体表达较高与总生存期较长相关（P = 0.041）。α-2巨球蛋白、CD163、柯萨奇病毒和腺病毒受体、叉头框J2和syntaxin 12的受试者工作特征曲线下面积（AUC）分别为0.975、0.705、0.917、0.997和0.956。
本研究是首次对ICC进行蛋白质组MR分析，揭示了其复杂的遗传结构，并鉴定出五种与该疾病有潜在因果关系的新型血液蛋白质。通过蛋白质组MR分析、scRNA-seq分析以及使用TCGA和GTEx数据库进行诊断预后评估，这些蛋白质被评估为有前景的治疗和诊断靶点。这些发现为未来ICC治疗策略提供了理论基础。
