Clinical characterization and therapeutic targets of vitamin A in patients with hepatocholangiocarcinoma and coronavirus disease

Abstract

Recent reports indicate that patients with hepatocholangiocarcinoma (CHOL) have a higher morbidity and mortality rate for coronavirus disease (COVID-19). Anti-CHOL/COVID-19 medicines are inexistent. Vitamin A (VA) refers to a potent nutrient with anti-cytotoxic and anti-inflammatory actions. Therefore, this study aimed to determine the potential functions and molecular mechanisms of VA as a potential treatment for patients with both CHOL and COVID-19 (CHOL/COVID-19). The transcriptome data of CHOL patients were obtained from the Cancer Genome Analysis database. Furthermore, the network pharmacology approach and bioinformatics analysis were used to identify and reveal the molecular functions, therapeutic biotargets, and signaling of VA against CHOL/COVID-19. First, clinical findings identified the medical characteristics of CHOL patients with COVID-19, such as susceptibility gene, prognosis, recurrence, and survival rate. Anti-viral and anti-inflammatory pathways, and immunopotentiation were found as potential targets of VA against CHOL/COVID-19. These findings illustrated that VA may contribute to the clinical management of CHOL/COVID-19 achieved by induction of cell repair, suppression of oxidative stress and inflammatory reaction, and amelioration of immunity. Nine vital therapeutic targets (BRD2, NOS2, GPT, MAPK1, CXCR3, ICAM1, CDK4, CAT, and TMPRSS13) of VA against CHOL/COVID-19 were identified. For the first time, the potential pharmacological biotargets, function, and mechanism of action of VA in CHOL/COVID-19 were elucidated.

Keywords: COVID-19; coronavirus disease; hepatocholangiocarcinoma; network pharmacology; vitamin A.

Figure 1

Identification of CHOL/COVID-19-assocaited genes. (A) Venn diagram depicted the number of intersecting genes in CHOL/COVID-19. (B) Volcano-plot showed the expression level of differential expressed genes (DEGs) found in CHOL. The genes with |log2 (fold change)| > 1 and -log10(FDR) > 1.3 were considered as DEGs.

Figure 2

Prognostic value of CHOL/COVID-19-associated genes. (A) Univariate Cox analysis of 7 CHOL/COVID-19-associated genes, including MRC1, CP, ITGA5, SNCA, HARS1, ENPP1, and PLAU. (p < 0.05). Hazard ratio represented the correlation of the identified genes and CHOL. (B) Survival analysis indicated no difference in the overall survival between high- and low-risk groups of CHOL patients. (C) Analysis of patients’ risk score using Cox proportional hazards regression showed the increasing risk score in the CHOL patients with high risk. (D) Heatmap showed the overexpression of CP, HARS1 and PLAU in the CHOL patients with high risk as compared to those with low risk. (E) The CHOL patients from high-risk group had a poor overall survival rate as compared to those from low-risk group.

Figure 3

Identification and functional characterization of CHOL/COVID-19/Vitamin A-associated genes. (A) Venn diagram showed the number of intersecting genes of vitamin A and CHOL/COVID-19. (B) Gene ontology enrichment analysis highlighted the biological processes affected by the VA/CHOL/COVID-19-associated genes. (C) The bubble diagram showed the involvement of genes in different biological processes. (D) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis demonstrated the alteration of cell signaling pathways by the VA/CHOL/COVID-19-associated genes. (E) The bubble diagram showed the involvement of genes in different cell signaling pathways. (F) Interaction network showed core biotargets, pharmacological functions, and signaling pathways of VA against CHOL/COVID-19.VA.

Figure 4

Gene network analysis of vitamin A against CHOL/COVID-19. (A) STRING analysis indicated protein-protein interaction mediated by 9 intersecting genes of VA against CHOL/COVID-19. (B) Cytoscape analysis further showed the involvement of 6 core candidates including CAT, NOS2, CXCR3, MAPK1, GPT, and ICAM1 in protein interaction network related to action of VA against CHOL/COVID-19.

Figure 5

MetaboAnalyst analysis showed the targeted metabolic pathways by VA against CHOL/COVID-19.