Therapeutic targets for hepatocellular carcinoma identified using proteomics and Mendelian randomization

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

doi:10.1111/jgh.16785

Therapeutic targets for hepatocellular carcinoma identified using proteomics and Mendelian randomization

J Gastroenterol Hepatol. 2024 Oct 30. doi: 10.1111/jgh.16785. Online ahead of print.

Authors

Weixiong Zhu^{1

2}, Chuanlei Fan³, Bo Liu^{1

2}, Jianqi Qin^{1

2}, Aodong Fan^{1

2}, Zengxi Yang^{1

2}, Hui Zhang^{1

2}, Wence Zhou^{1

2}

Affiliations

¹ The Second Hospital and Clinical Medical School, Lanzhou University, Lanzhou, China.
² Department of General Surgery, The Second Hospital of Lanzhou University, Lanzhou, China.
³ Nanchang Central Hospital, Jiangxi Provincial University of Traditional Chinese Medicine, nanchang, 330000, China.

PMID: 39477889
DOI: 10.1111/jgh.16785

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.

Keywords: drug target; enrichment pathway analysis; hepatocellular carcinoma; proteome‐wide Mendelian randomization; single‐cell‐type expression analysis.

Abstract

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