CAMK1D as a potential therapeutic target for gut microbiota-driven promotion of lung adenocarcinoma development

The gut microbiome is closely associated with malignant tumors; however the specific mechanisms by which it contributes to the development of lung adenocarcinoma remain unclear. In this study, we performed a two-sample bidirectional Mendelian randomization (MR) analysis to assess the causal relationship between the gut microbiome and lung adenocarcinoma. By identifying single nucleotide polymorphism markers linked to gut microbiome species, we aimed to discover potential biomarkers for lung adenocarcinoma. These findings may offer new insights into the role of the gut microbiome in the prevention and treatment of lung adenocarcinoma.

We used genome-wide association study (GWAS) summary statistics to assess the association between the gut microbiome and lung adenocarcinoma through two-sample MR analysis. Sensitivity analyses were performed to confirm the robustness of the findings. Reverse MR analysis and GWAS data integration were employed to identify potential genetic and therapeutic targets. Bioinformatics analysis and quantitative Real-Time PCR (qRT-PCR) were utilized to validate gene expression and explore the underlying mechanisms of key genes.

Our analysis identified two bacterial taxa, Prevotella9 and Parabacteroides, as being causally associated with lung adenocarcinoma, both showing positive causal relationships. Sensitivity analyses confirmed the robustness of these associations. The reverse MR analysis revealed no evidence of reverse causality. GWAS data identified 15 genes (DNAH1, PDE10A, DOCK2, INSYN2B, DNAI3, SUOX, LINC01505, SULT4A1, NT5ELP, LINC02895, calcium/calmodulin dependent protein kinase 1D (CAMK1D), ENSG00000253557, BCAS3, C18orf63, MYO18B) that passed the summary-data-based MR test. The transcriptomic data revealed that five genes (CAMK1D, BCAS3, DNAH1, PDE10A, and C18orf63) were differentially expressed between lung adenocarcinoma patients and healthy individuals. Through qRT-PCR validation, the CAMK1D gene was markedly upregulated in lung adenocarcinoma cell lines, whereas BCAS3, DNAH1, PDE10A, and C18orf63 genes exhibit ed substantially reduced expression.

Our study identified specific gut microbial taxa as risk factors for lung adenocarcinoma and proposes CAMK1D as a microbiota-related candidate biomarker and potential therapeutic target that may inform personalized treatment and drug development strategies in the future.