Therapeutic targets for hepatocellular carcinoma identified using proteomics and Mendelian randomization

IF 3.4 3区医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Journal of Gastroenterology and Hepatology Pub Date : 2024-10-30 DOI:10.1111/jgh.16785

Weixiong Zhu, Chuanlei Fan, Bo Liu, Jianqi Qin, Aodong Fan, Zengxi Yang, Hui Zhang, Wence Zhou

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Abstract

Background and Aim

Hepatocellular carcinoma (HCC) emerges as a formidable malignancy marked by elevated morbidity and mortality rates, coupled with a dismal prognosis. The revelation of gene–protein associations has presented an avenue for the exploration of novel therapeutic targets.

Methods

Pooling plasma proteomic data (seven published GWAS) and HCC data (DeCODE cohort), we applied MR to identify potential drug targets, which were further validated in the FinnGen cohort and UK Biobank. Subsequent colocalization and summary-data-based Mendelian randomization analyses were performed for potential associations of this set of proteins. In addition, enrichment information pathways were investigated in depth by KEGG pathway analysis, single-cell sequencing, PPI and DGIdb, ChEMBL, and DrugBank database analyses, specific cell types enriched for expression were identified, interacting proteins were identified, and finally, druggability was assessed.

Results

In summary, the levels of 10 proteins are linked to HCC risk. Elevated levels of TFPI2 as well as decreased levels of ALDH1A1, KRT18, ADAMTS13, TIMD4, SCLY, HRSP12, TNFAIP6, FTCD, and DDC are associated with increased HCC risk. Notably, HRSP12 show the strongest evidence. These genes are primarily expressed in specific cell types within the HCC TME. Moreover, intricate protein–protein interactions, involving key players like ALDH1A1 and RIDA, ALDH1A1 and DDC, and ALDH1A1 and KRT18, contribute significantly to the amino acid metabolism and dopaminergic neurogenesis pathway. Proteins such as ALDH1A1, KRT18, TFPI2, and DDC are promising targets for HCC therapy and broader cancer drug development. Targeting these proteins offers substantial potential in advancing HCC treatment strategies.

Conclusions

This research delineates 10 protein biomarkers linked to HCC risk and offers novel perspectives on its etiology, as well as promising avenues for the screening of HCC protein markers and therapeutic agents.

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利用蛋白质组学和孟德尔随机化确定肝细胞癌的治疗靶点。

背景和目的：肝细胞癌（HCC）是一种可怕的恶性肿瘤，发病率和死亡率都很高，而且预后不佳。基因与蛋白质关联的揭示为探索新的治疗靶点提供了一条途径：方法：我们汇集了血浆蛋白质组数据（已发表的七项 GWAS）和 HCC 数据（DeCODE 队列），应用磁共振技术识别潜在的药物靶点，并在 FinnGen 队列和英国生物库中进一步验证了这些靶点。随后，我们对这组蛋白质的潜在关联性进行了共定位和基于汇总数据的孟德尔随机分析。此外，还通过 KEGG 通路分析、单细胞测序、PPI 和 DGIdb、ChEMBL 和 DrugBank 数据库分析深入研究了富集信息通路，确定了富集表达的特定细胞类型，确定了相互作用的蛋白质，最后评估了可药用性：总之，10 种蛋白质的水平与 HCC 风险有关。TFPI2水平的升高以及ALDH1A1、KRT18、ADAMTS13、TIMD4、SCLY、HRSP12、TNFAIP6、FTCD和DDC水平的降低与HCC风险的增加有关。值得注意的是，HRSP12 显示了最有力的证据。这些基因主要在 HCC TME 中的特定细胞类型中表达。此外，ALDH1A1 和 RIDA、ALDH1A1 和 DDC 以及 ALDH1A1 和 KRT18 等关键蛋白参与了错综复杂的蛋白间相互作用，对氨基酸代谢和多巴胺能神经发生途径做出了重要贡献。ALDH1A1、KRT18、TFPI2 和 DDC 等蛋白是治疗 HCC 和开发更广泛的抗癌药物的理想靶点。针对这些蛋白的研究为推进 HCC 治疗策略提供了巨大的潜力：这项研究界定了与 HCC 风险相关的 10 种蛋白质生物标记物，为 HCC 病因学提供了新的视角，也为筛选 HCC 蛋白质标记物和治疗药物提供了前景广阔的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Gastroenterology and Hepatology 医学-胃肠肝病学

CiteScore

7.90

自引率

2.40%

发文量

326

审稿时长

2.3 months

期刊介绍： Journal of Gastroenterology and Hepatology is produced 12 times per year and publishes peer-reviewed original papers, reviews and editorials concerned with clinical practice and research in the fields of hepatology, gastroenterology and endoscopy. Papers cover the medical, radiological, pathological, biochemical, physiological and historical aspects of the subject areas. All submitted papers are reviewed by at least two referees expert in the field of the submitted paper.