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Bioinformatics-Based Analysis of the Screening and Evaluation of Potential Targets of FTY720 for the Treatment of
Mengyuan Han1,2,3,4,5, Sendaer Hailati1,3,4,5, Dilihuma Dilimulati1,3,4,5
1Department of Pharmacology, School of Pharmacy, Xinjiang Medical University, Urumqi 830017, China.
Background:
A range of cancer cells are significantly inhibited by FTY720. It is unknown, nevertheless, how FTY720 influences the onset of non-small cell lung cancer (NSCLC). Using bioinformatics techniques, we analyzed and the possible molecular mechanisms and targets of FTY720 for the treatment of NSCLC.
Methods:
DEGs (Differentially expressed genes) were acquired by differential analysis of the dataset GSE10072. Obtained FTY720 target genes and NSCLC disease genes from databases such as Swiss-TargetPrediction and GeneCard. Subsequently, target and disease genes, as well as DEGs, were merged for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, gene ontology (GO), and protein interaction analysis. The overlapping genes of DEGs and target genes, and disease genes were also obtained separately and subjected to survival as well as expression analyses. We constructed the regulatory network of miRNAs and transcription factors (TFs) on hub genes. Finally, the immune cell association of hub genes was evaluated using the ssGSEA method, molecular docking of FTY720 to hub genes was carried out utilizing Autodock, and molecular dynamics simulations were conducted.
Results:
In this study, 444 DEGs, 232 target genes of FTY720, and 466 disease genes were obtained. Moreover, a total of 1062 genes were obtained by removing duplicate values after merging, among which PIK3R1, Akt1, and S1PR1 had the highest DEGREE values in the protein interactions network, and these genes were primarily enriched in MAPK, PI3K-Akt signaling pathways, with the PI3K-Akt signaling pathway being the most prominent. Among the overlapping genes, three potential targets of FTY720 for NSCLC treatment were found: S1PR1, ZEB2, and HBEGF. ZEB2 and S1PR1 were determined to be hub genes and to significantly affect NSCLC prognosis by survival analysis. Furthermore, hsa-miR-132-3p, hsa-miR-192-5p, and hsa-miR-6845-3p were strongly associated with FTY720 for the treatment of NSCLC; CTBP1 (carboxy-terminal binding protein 1), EZH2 (protein lysine N-methyltransferase), and ZNF610 (zinc-finger protein 610) may all influence the expression of ZEB2 and S1PR1. Hub genes had a substantial negative link with memory B cells and a significant positive correlation with memory CD8 T cells and Th17 helper T cells. The molecular docking and kinetic simulation results of FTY720 with the two hub genes indicate that the protein-ligand complex has good stability.
Conclusion:
Our research indicates that FTY720 may inhibit NSCLC via possible targets ZEB2 and S1PR1, further laying the theoretical foundation for the utilization of FTY720 in NSCLC treatment.
Insights
FTY720 shows potential in treating non-small cell lung cancer (NSCLC) by targeting ZEB2 and S1PR1. This study elucidates the molecular mechanisms, providing a foundation for FTY720
Area of Science:
- Oncology
- Bioinformatics
- Pharmacology
Background:
- FTY720 demonstrates significant inhibition across various cancer cells.
- The specific impact of FTY720 on non-small cell lung cancer (NSCLC) onset remains unclear.
- This study investigates the molecular mechanisms and potential targets of FTY720 in NSCLC treatment using bioinformatics.
Purpose of the Study:
- To identify potential molecular targets of FTY720 in non-small cell lung cancer (NSCLC).
- To elucidate the molecular mechanisms underlying FTY720's effect on NSCLC.
- To provide a theoretical basis for FTY720's application in NSCLC therapy.
Main Methods:
- Differential gene expression analysis of NSCLC dataset GSE10072.
- Integration of FTY720 target genes and NSCLC disease genes from databases.
- Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analysis.
- Protein-protein interaction network construction and hub gene identification.
- Survival and expression analyses of overlapping genes.
- Construction of miRNA and transcription factor regulatory networks.
- ssGSEA for immune cell association analysis.
- Molecular docking and dynamics simulations of FTY720 with identified hub genes.
Main Results:
- Identified 444 differentially expressed genes (DEGs), 232 FTY720 target genes, and 466 NSCLC disease genes.
- PIK3R1, Akt1, and S1PR1 emerged as key nodes in the protein interaction network, primarily linked to MAPK and PI3K-Akt signaling pathways.
- ZEB2 and S1PR1 were identified as significant hub genes affecting NSCLC prognosis and potential direct targets of FTY720.
- FTY720 showed stable binding with ZEB2 and S1PR1 through molecular docking and simulations.
- Hub genes exhibited significant correlations with specific immune cell populations, including memory B cells, CD8 T cells, and Th17 cells.
Conclusions:
- FTY720 potentially inhibits NSCLC through targeting ZEB2 and S1PR1.
- The identified molecular mechanisms and targets lay the groundwork for FTY720's clinical application in NSCLC.
- Further research is warranted to validate these findings and explore therapeutic strategies.
