Identification of hsa-miR-193a-5p-SURF4 axis related to the gut microbiota-metabolites- cytokines in lung cancer based on Mendelian randomization study and bioinformatics analysis

Abstract

Abstract Background Lung cancer is a significant disease that affects people's physical and mental health. Currently, the treatment outcomes still do not meet clinical needs, and the causes of the disease are still unclear, therefore further exploration is needed. Methods We analyzed the exposure factors of lung cancer, including gut microbiota, serum metabolites, and cytokines, through Mendelian randomization studies and bioinformatics analysis. We identified common SNPs and performed gene annotation, leading to the discovery of the key gene SURF4, which may affect the onset of lung cancer. We validated the oncogenic function and mechanism of SURF4 through public data analysis using GO and KEGG, and constructed a ceRNA network, revealing the lung cancer oncogenic pathway involving lncRNA/pseudogene-microRNA-SURF4. Results We first conducted a Mendelian randomization analysis on 418 gut microbiota, 1400 serum metabolites, and 41 cytokines in relation to lung cancer. We found that 16 gut microbiota, 29 serum metabolites, and 2 cytokines were closely associated with lung cancer. Further comparison of all differential SNPs revealed that rs550057 on chromosome 9 was a common SNP among these three exposure factors, indicating its crucial role in lung cancer formation. Through gene functional annotation using R language, we found that the expression of 15 genes, including SURF4, was influenced by rs550057. By querying these 15 genes from public databases for their differential expression and prognosis in lung cancer, we found significant differences in SURF4, MED22, and RPL7A. Furthermore, by querying the expression and correlation coefficients of upstream microRNAs of these three genes through the starBase website, we found that hsa-miR-193a-5p-SURF4 had the most significant effect on lung cancer. Through GO and KEGG analysis of SURF4-related genes, we identified the molecular pathways associated metabolic synthesis and microbial infection related to the promotion of lung cancer by SURF4. This validated the results of the previous Mendelian randomization study. Furthermore, we constructed a ceRNA network for SURF4 and identified two upstream differentially expressed pseudogenes and nine lncRNAs, confirming the functionality of the pseudogene/lncRNA-microRNA-SUFR4 pathway. Conclusions In summary, we have elucidated the regulatory role of the pseudogene/lncRNA-microRNA-SUFR4 pathway in the progression of lung cancer, combining the research hotspots of gut microbiota-serum metabolites-cytokines. We have also confirmed the pathway and mechanism through SURF4 and its related genes promoting lung cancer formation. This may provide effective therapeutic methods for lung cancer and serve as a potential prognostic marker.

Keywords

• Mendelian randomization
• Bioinformatics analysis
• Lung cancer
• Gut microbiota
• Metabolites
• Cytokines