PO.PR01.03 · 预防研究
血浆蛋白质组学分析揭示英国生物样本库中MASLD相关肝细胞癌与消化道肿瘤的共有生物标志物
Plasma proteomic profiling reveals shared biomarkers for MASLD-related hepatocellular carcinoma and gastrointestinal cancers in the UK Biobank
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摘要 Abstract
中文摘要
背景：代谢功能障碍相关脂肪性肝病（MASLD）是一项重大的全球健康挑战，并显著升高肝细胞癌（HCC）及肝外消化道（GI）肿瘤的风险。目前在MASLD人群中用于早期检测的可靠生物标志物仍然缺乏。我们利用英国生物样本库（UK Biobank）的大规模血浆蛋白质组学数据，以鉴定MASLD相关HCC及GI肿瘤的循环蛋白标志物。
方法：我们在UK Biobank内开展了一项巢式病例对照研究。鉴定差异表达的血浆蛋白，并采用基因本体论（Gene Ontology）、京都基因与基因组百科全书（KEGG）通路富集分析以及蛋白质-蛋白质相互作用（PPI）网络分析进行评估。将不同癌种间重叠的失调蛋白进行映射，以确定共有通路。
结果：UK Biobank队列纳入了19,341例具有蛋白质组学数据的MASLD患者（平均年龄61.1 ± 6.3岁），其中包括40例MASLD-HCC病例和589例MASLD-GI病例。在排除蛋白数据缺失率超过30%的样本后，本研究纳入33例MASLD-HCC病例和516例MASLD-GI肿瘤病例，分别按年龄和性别以1:3比例匹配至99例和1,548例MASLD对照。定量蛋白质组学在MASLD-HCC与MASLD的比较中鉴定出45种显著失调蛋白（44种上调，1种下调），包括已确立的HCC相关角蛋白（如KRT8、KRT18）和新型候选蛋白（如SPINT3、ADGRG1）。富集通路凸显了脂质代谢功能障碍和异生物质代谢。IL-6和AGXT成为PPI网络中的核心枢纽基因。在MASLD-GI肿瘤中，24种蛋白发生显著改变。值得注意的是，14种蛋白在MASLD-HCC和MASLD-GI肿瘤中均一致失调，包括CDHR2、INSL3、GPRC5C、FGF21、MME、CES1、KRT18、ADGRG1、HAO1、KLK3、GAST和FOLR3。
结论：这项大规模前瞻性蛋白质组学研究勾勒出MASLD相关肿瘤既独特又重叠的血浆蛋白特征。共有的生物标志物映射至一条统一的“代谢-损伤-炎症”轴，提示MASLD癌变的共同机制。这些发现提供了一个颇具前景的生物标志物组合，在MASLD人群的多癌种早期检测和风险分层中具有潜在应用价值。
查看英文原文 English abstract
Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health challenge and markedly elevates the risk of hepatocellular carcinoma (HCC) and extrahepatic gastrointestinal (GI) cancers. Reliable biomarkers for early detection in MASLD populations remain lacking. We leveraged large-scale plasma proteomic profiling from the UK Biobank to identify circulating protein markers for MASLD-related HCC and GI cancers.
Methods: We performed a nested case-control study within the UK Biobank. Differentially expressed plasma proteins were identified and evaluated using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and protein-protein interaction (PPI) network analyses. Overlapping dysregulated proteins between cancer types were mapped to determine shared pathways.
Results: The UK Biobank cohort included 19,341 MASLD patients with proteomics data (mean age 61.1 ± 6.3 years), comprising 40 MASLD-HCC cases and 589 MASLD-GI cases. After excluding samples with protein data missing rates exceeding 30%, the study included 33 MASLD-HCC cases and 516 MASLD-GI cancer cases, matched 1:3 by age and sex to 99 and 1,548 MASLD controls, respectively.Quantitative proteomics identified 45 significantly dysregulated (44 upregulated and 1 downregulated) proteins in MASLD-HCC compared to MASLD, including established HCC-related keratins (e.g., KRT8, KRT18) and novel candidates (e.g., SPINT3, ADGRG1). Enriched pathways highlighted lipid metabolic dysfunction and xenobiotic metabolism. IL-6 and AGXT emerged as central hub genes in the PPI network. In MASLD-GI cancers, 24 proteins were significantly altered. Notably, 14 proteins were consistently dysregulated across both MASLD-HCC and MASLD-GI cancers, including CDHR2, INSL3, GPRC5C, FGF21, MME, CES1, KRT18, ADGRG1, HAO1, KLK3, GAST, and FOLR3.
Conclusion: This large prospective proteomic study delineates distinct and overlapping plasma protein signatures of MASLD-related cancers. The shared biomarkers map to a unified "metabolism-damage-inflammation" axis, suggesting common mechanisms underlying carcinogenesis in MASLD. These findings provide a promising biomarker panel with potential utility for multi-cancer early detection and risk stratification in MASLD populations.
利益披露 Disclosure
Q. Wang, None..
Y. Zhang, None..
K. Chen, None.