Abstract
BACKGROUND: Lung squamous cell carcinoma (LUSC) is one of the most prevalent subtypes of lung cancer, accounting for approximately 25%. Mendelian randomization (MR) analysis of plasma proteins can identify potential drug targets for LUSC. METHODS: We obtained genetic instruments for plasma proteins from a GWAS by Sun BB et al. conducted on 3301 healthy adults. GWAS summary statistics of LUSC were from ILCCO. We conducted a two-sample MR analysis to investigate the causal relationships between plasma proteins and the risk to LUSC. Colocalization analysis was used to test whether two traits share the same causal variables. Survival analysis based on potential proteins was conducted using transcriptomic data from TCGA database to determine whether gene expression levels are associated with the prognosis of LUSC patients. Moreover, predictions of potential drug ligands and molecular dockings were performed to evaluate the pharmaceutical properties of the target genes. RESULTS: Proteome-wide MR analysis identified three proteins (MICB, SPINK2, TXNDC11) that showed a strong association with decreased risk of LUSC after FDR correction. Increased levels of MICB [OR(95% CI) = 0.72(0.63, 0.83); p = 3.90E-06], SPINK2 [OR (95% CI) = 0.74 (0.66, 0.84); p = 1.25E-06], TXNDC11 [OR (95% CI) = 0.63(0.51, 0.78); p = 2.69E-05] per SD decreased the risk of LUSC specifically. Sensitivity analysis revealed that there was no significant heterogeneity, pleiotropy, or reverse causality between these proteins and LUSC. Colocalization analysis indicated that three proteins shared the same variants with LUSC. Survival analysis showed that upregulation of SPINK2 was associated with a favorable prognosis in LUSC patients, while MICB and TXNDC11 were not. The expression of MICB, SPINK2, TXNDC11 was found to be potentially affected by specific substances, and our molecular docking showed a stable binding between SPINK2 and danazol, suggesting its potential as a drug target. CONCLUSION: This study identified SPINK2 causally associated with the risk and prognosis of LUSC, which is a promising target for LUSC. The drug prediction we performed illustrated the medicinal potential of SPINK2, and the high binding activity of molecular docking indicated its strong potential as a drug target.