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. 2023 Mar 8:13:1151434.
doi: 10.3389/fonc.2023.1151434. eCollection 2023.

Discovery of therapeutic targets of quercetin for endometrial carcinoma patients infected with COVID-19 through network pharmacology

Kehan Li  1 , Hejing Liu  1 , Yibin Lin  1 , Liang Gu  2 , Xinli Xiang  1 , Xueqiong Zhu  1   2
Affiliations

Discovery of therapeutic targets of quercetin for endometrial carcinoma patients infected with COVID-19 through network pharmacology

Kehan Li et al. Front Oncol. .

Abstract

Purpose: Aimed to identify the anti-uterine corpus endometrial carcinoma (UCEC) function and characterize the mechanism of quercetin in the treatment of patients infected with COVID-19 via integrated in silico analysis.

Methods: The Cancer Genome Atlas and Genotype Tissue Expression databases were applied to obtain differentially expressed genes of UCEC and non-tumor tissue. Several in silico methods such as network pharmacology, functional enrichment analysis, Cox regression analyses, somatic mutation analysis, immune infiltration and molecular docking were used to investigate and analysis the biological targets, functions and mechanisms of anti-UCEC/COVID-19 of quercetin. Multiple methods such as CCK8 assay, Transwell assay and western blotting were performed to test proliferation, migration, and protein level of UCEC (HEC-1 and Ishikawa) cells.

Results: Functional analysis disclosed that quercetin against UCEC/COVID-19 mainly by 'biological regulation', 'response to stimulus', and 'regulation of cellular process'. Then, regression analyses indicated that 9 prognostic genes (including ANPEP, OAS1, SCGB1A1, HLA-A, NPPB, FGB, CCL2, TLR4, and SERPINE1) might play important roles in quercetin for treating UCEC/COVID-19. Molecular docking analysis revealed that the protein products of 9 prognostic genes were the important anti-UCEC/COVID-19 biological targets of quercetin. Meanwhile, the proliferation and migration of UCEC cells were inhibited by quercetin. Moreover, after treatment with quercetin, the protein level of ubiquitination-related gene ISG15 was decreased in UCEC cells in vitro.

Conclusions: Taken together, this study provides new treatment option for UCEC patients infected with COVID-19. Quercetin may work by reducing the expression of ISG15 and participating in ubiquitination-related pathways.

Keywords: COVID-19; network pharmacology (NP); quercetin; ubiquitination; uterine corpus endometrial carcinoma (UCEC).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The graphical abstract of this article. The figure represents the antiviral action and mechanism of quercetin against UCEC/COVID-19 using the network pharmacology and computational bioinformatics analysis approach.
Figure 2
Figure 2
Analysis of intersecting genes in UCEC/COVID-19. (A) The heatmap of differential expression about intersecting genes in UCEC/COVID-19. (B) The volcano plot depicting 138 DGEs. Red dots and green dots represent differentially expressed up-regulated and down-regulated genes, respectively.
Figure 3
Figure 3
Functional characterization of quercetin against UCEC/COVID-19 intersecting genes. (A) Venn diagram describing intersecting genes of quercetin and UCEC/COVID-19. (B) GO analysis of intersecting genes of quercetin and UCEC/COVID-19. (C) KEGG pathway analysis of intersecting genes of quercetin and UCEC/COVID-19.
Figure 4
Figure 4
Analysis of cluster 1 from PPI network. (A) Cluster 1 contained 25 genes. (B) BP results from GO enrichment analysis of Cluster 1. (C) KEGG pathway analysis of genes in Cluster 1. (D) Two genes in Cluster 1 were URGs.
Figure 5
Figure 5
The diseases-drug-targets network of quercetin treatment for UCEC/COVID-19 patients.
Figure 6
Figure 6
The risk coefficient model of UCEC predicted outcome. (A) The distribution of the risk scores of UCEC patients. (B) A Kaplan-Meier curve was constructed based on the survival status of the high- and low-risk groups. (C) The time-dependent curve showed that the AUC values at year 1, 2, and 3 were separated 0.680, 0.681, and 0.673, respectively.
Figure 7
Figure 7
Heatmap and clinicopathologic parameters. (A) The clinical heatmap of 9 risk prognostic genes. (B) The risk scores were higher in the grade 3 and older patients. * means P< 0.05; ** means P< 0.01; *** means P< 0.001.
Figure 8
Figure 8
The relationship between prognostic gene levels and clinical characteristics. The relationship between the expression of OAS1 and grade (A), stage (B), and age (C) of UCEC patients. The relationship between the expression of SCGB1A1 and grade (D), stage (E) of UCEC patients. The relationship between the expression of HLA-A and grade (F), stage (G) of UCEC patients. The relationship between the expression of TLR4 and grade (H), stage (I), and age (J) of UCEC patients. The relationship between the expression of SERPINE1 and grade (K), age (L) of UCEC patients. * means P< 0.05; ** means P< 0.01; *** means P< 0.001.
Figure 9
Figure 9
Landscape of mutations in 57 genes in UCEC. The left panel represents 9 prognostic genes which ordered by their mutation frequencies. The bottom panel represents 10 types of mutation.
Figure 10
Figure 10
Correlation of 9 prognostic genes with immune cells in UCEC. (A) ANPEP, (B) OAS1, (C) SCGB1A1, (D) HLA‐A, (E) NPPB, (F) FGB, (G) CCL2, (H) TLR4, and (I) SERPINE1.
Figure 11
Figure 11
Immune cell infiltration influenced by copy number variation of prognostic genes. (A) ANPEP, (B) OAS1, (C) SCGB1A1, (D) NPPB, (E) FGB, (F) CCL2, (G) TLR4, and (H) SERPINE1.
Figure 12
Figure 12
The protein expression of prognostic genes in UCEC tissues and normal endometrial tissues. (A) ANPEP, (B) OAS1, (C) SCGB1A1, (D) FGB, and (E) CCL2.
Figure 13
Figure 13
Schematic diagram of molecular docking between quercetin and 7BQY.
Figure 14
Figure 14
Quercetin inhibits the proliferation and migration of UCEC cells and reduces the expression of ISG15. (A) Quercetin suppressed viability of HEC-1 and Ishikawa cells by CCK-8 assay. (B) Left panel: Transwell assays were used in HEC-1 and Ishikawa cells with or without quercetin. Right panel: Quantitative analyses for Transwell assays. (C) Western blotting showed quercetin reduced the expression of ISG15. The bar graph showed the ratio of ISG15 level between quercetin treatment group and control group. * means P< 0.05; ** means P< 0.01; *** means P< 0.001.
Figure 15
Figure 15
The schematic model illustrates how quercetin plays an anti-cancer role in UCEC.
See this image and copyright information in PMC

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