Abstract:

Objective To discuss the mechanism of salidroside in the treatment of triple negative breast cancer （TNBC） by using the bioinformatics and network pharmacology methods， and to clarify the main targets and signaling pathways involved in the therapeutic effect. Methods The dataset GSE45827 was obtained from the Gene Expression Omnibus （GEO） database； the gene set enrichment analysis （GSEA） was performed by using the R software package GSEABase；the differentially expressed genes （DEGs） between the adjacent normal tissue and TNBC tissue were identified by limma R software package；the Gene Ontology （GO） functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes （KEGG） signaling pathway enrichment analysis were performed on the DEGs， and the DEGs were integrated with the drug targets to import into gene/protein interaction retrieval tool String database， and the protein-protein interaction （PPI） networks were constructed；the functional module screening of the PPI network was conducted by MCODE plugin， and the top 2 modules ranked by SCORE value were further subjected to GO functional enrichment analysis and KEGG signaling pathway analysis. The pathways obtained from the two rounds of KEGG enrichment analysis were intersected with the results of GSEA enrichment analysis to identify the pathways involved in the therapeutic effect of salidroside on TNBC. The top 10 key node genes in the highest scoring module determined by the maximum clique centrality （MCC） score caculated by CytoHubba plugi were considered as the core genes； the molecular docking was performed by AutoDock Vina1.1.2 and PyMOL2.3.0 Software. Results The intersection of KEGG and GSEA enrichment analysis results showed 13 singaling pathways， including the cell cycle， cellular senescence， and p53 signaling pathways，and so on. The biological processes involved in the GO functional analysis， such as mitosis， nuclear division， and sister chromatid separation， were closely related to the cell cycle and consistented with the results of the KEGG signaling pathway enrichment analysis. The top ranked module based on the SCORE value contained 5 drug target genes of Rhodiola glycoside，such as cyclin A2 （CCNA2）， checkpoint kinase 1 （CHEK1）， kinesin family member 11 （KIF11）， DNA topoisomerase 2-alpha （TOP2A）， and thymidylate synthase （TYMS）. The molecular docking results demonstrated strong binding affinities between the above proteins and Rhodiola glycoside （binding energy<－7.0 kcal·mol^－1）. Conclusion The tightly binding target of salidroside is located in the key functional modules of DEGs of TNBC， which can directly regulate by binding with CCNA2 and protein， and indirectly regulate the key differentially genes of TNBC by binding with KIF11， TOPA2， CHEK1 and TYMS proteins. Therefore， salidroside may be a potential clinical therapeutic drug for TNBC.

Key words: Salidroside, Triple negative breast cancer, Bioinformatics, Network pharmacology, Molecular docking