Unraveling the causal relationship and underlying mechanisms between cathepsins on liver cancer: findings from mendelian randomization and bioinformatics analysis
Mar 7, 2025Discover oncology
How cathepsin enzymes may influence liver cancer risk and their underlying biological roles
Cathepsin F (CTSF) is associated with a decreased risk of hepatic bile duct cancer (HBDC) with an of 0.826.
CTSF may play protective roles in patients with HBDC.
Lower expression of CTSF genes is observed in patients with HBDC.
Functional enrichment analysis indicates CTSF is related to the cell cycle and P53 pathway in HBDC.
CTSF demonstrates good binding ability with MDM2, a key negative regulator of p53.
No heterogeneity or pleiotropy was identified in the analysis.
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BACKGROUND: Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are two major types of primary liver cancer (PLC). Earlier research has indicated a potential link between cathepsins and liver cancer. Nonetheless, there have been limited clinical trials examining the connection between cathepsins and PLC. Therefore, we conducted a two-sample (MR) study to evaluate the causal relationship between cathepsins and PLC.
METHODS: Data from genome-wide association studies (GWAS) focusing on cathepsins was collected. Additionally, summary data for GCST90018803 (Hepatic bile duct cancer, HBDC), and GCST90018858 (related to hepatic cancer, HC), were employed in the discovery and validation phases of the study, respectively. The inverse variance weighted (IVW) method was served as the primary analytical method in our Mendelian randomization (MR) study, supplemented by the MR-Egger, weighted median, simple mode, and weighted mode methods. To assess heterogeneity and pleiotropy, we conducted the MR-Egger intercept test, Cochran's Q test, as well as the MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) analysis, along with the leave-one-out analysis. After that, bioinformatic analysis based on the Gene Expression Omnibus (GEO) databases were utilized, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis were utilized for exploring the underlying mechanisms. Additionally, protein-protein docking was employed to confirm the interaction between related proteins.
RESULTS: The results showed that cathepsin F (CTSF), was causally associated with HBDC. CTSF decrease the risk of HBDC ( = 0.826, 95% CI 0.711-0.959, P = 0.012). CTSF may play protective roles in patients with HBDC. No heterogeneity or pleiotropy was observed. Additionally, the expression of CTSF genes is lower in patients with HBDC, GO and KEGG functional enrichment analysis revealed CTSF were mainly related to cell cycle, and P53 pathway in HBDC. Docking results showed that CTSF had good binding ability with MDM2, the most well-established negative regulator of p53.
CONCLUSION: This study provided new evidence of the relationship between CTSF and HBDC, suggesting that CTSF plays an inhibition role in HBDC progression. CTSF could be a novel and effective way to for HDBC treatment.
Key numbers
0.826
Decrease in HBDC Risk
for the association between CTSF and HBDC
832 of 475,259
Cohort Size
Number of cases in the study for Hepatic bile duct cancer
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