Screening of flavonoids in Litchi Semen and its targets of intervention in colonic adenocarcinoma by weighted gene co-expression network analysis and molecular docking / 中草药

ABSTRACT

Objective: To screen the flavonoid constituents and targets of Litchi Semen in the intervention of progression and metastasis of colon adenocarcinoma (COAD). Methods: Through DRAR-CPI and SWISS database, potential targets of 19 flavonoids in Litchi Semen were searched. COAD gene expression data and clinical characteristic data from TCGA database were downloaded. Weighted gene co-expression network analysis (WGCNA) was used to establish the gene co-expression network and identify the co-expression module of COAD. The common targets of co-expression module and potential targets were used as the compound to interfere with the drug target of COAD. Protein interaction network analysis, KEGG and GO analysis were performed by String database. The Hub gene was extracted as potential biomarkers of COAD by the cytoHubba, and the interaction network of components, targets and pathways was established by the Cytoscape. The expressions of potential biomarkers were verified by HPA database, and the compounds were docked with the potential biomarkers. Results: A total of 18 co-expression modules were identified with seven of them were correlated with clinical features, such as survival time and tumor stage. Turquoise module was related to the development and transfer of COAD. 19 flavonoids in Litchi Semen acted on 380 potential targets. 34 targets repeated with turquoise module were selected as targets. GO analysis showed that the target points were enriched in 304 GO items, including 229 biological processes, 31 cell composition and 44 molecular functions; KEGG analysis showed that target points were enriched in cancer pathways, cell cycle, and progesterone-mediated 40 pathways including oocyte cancer pathway, cell senescence, and p53 signaling pathway. The genes of CDC25A, CDC25C, CCNB2 and AURKB were screened by cytoHubba as potential biomarkers which related to the progress and transfer of COAD. Compared with para-cancerous tissues, immunohistochemistry results obtained from HPA database showed that the protein expressions of CDC25C, AURKB and CCNB2 in COAD were increased significantly (P < 0.05), which were consistent with gene expression in TCGA data set. Narirutin, procyanidin A2, phloridzin and ent-epicatechin which were well combined to CDC25A, CDC25C and AURKB through hydrogen bond were screened. Conclusion CDC25A, CDC25C, CCNB2 and AURKB were the potential biomarkers closely related to the progression and metastasis of COAD. The mechanism of intervention of flavonoids in Litchi Semen on the progression and metastasis of COAD may be related to the regulation of biological processes, such as cell division, G2/M phase transformation of cell cycle, and the regulation of cancer pathway, p53 signaling pathway and other signaling pathways. Narirutin, procyanidin A2, phloridzin, ent-epicatechin and rutin could be treated as potential inhibitors of CDC25A, CDC25C and AURKB.