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. 2022 Sep 25:2022:1043445.
doi: 10.1155/2022/1043445. eCollection 2022.

CASP9 As a Prognostic Biomarker and Promising Drug Target Plays a Pivotal Role in Inflammatory Breast Cancer

Mingdi Zhang  1 , Kejin Wu  1 , Maoli Wang  1 , Fang Bai  1 , Hongliang Chen  1
Affiliations

CASP9 As a Prognostic Biomarker and Promising Drug Target Plays a Pivotal Role in Inflammatory Breast Cancer

Mingdi Zhang et al. Int J Anal Chem. .

Abstract

Background: Inflammatory breast cancer (IBC) is one of the most rare and aggressive subtypes of primary breast cancer (BC). Our study aimed to explore hub genes related to the pathogenesis of IBC, which could be considered as novel molecular biomarkers for IBC diagnosis and prognosis. Material and Methods. Two datasets from gene expression omnibus database (GEO) were selected. Enrichment analysis and protein-protein interaction (PPI) network for the DEGs were performed. We analyzed the prognostic values of hub genes in the Kaplan-Meier Plotter. Connectivity Map (CMap) and Comparative Toxicogenomics Database (CTD) was used to find candidate small molecules capable to reverse the gene status of IBC.

Results: 157 DEGs were selected in total. We constructed the PPI network with 154 nodes interconnected by 128 interactions. The KEGG pathway analysis indicated that the DEGs were enriched in apoptosis, pathways in cancer and insulin signaling pathway. PTEN, PSMF1, PSMC6, AURKB, FZR1, CASP9, CASP6, CASP8, BAD, AKR7A2, ZNF24, SSX2IP, SIGLEC1, MS4A4A, and VSIG4 were selected as hub genes based on the high degree of connectivity. Six hub genes (PSMC6, AURKB, CASP9, BAD, ZNF24, and SSX2IP) that were significantly associated with the prognosis of breast cancer. The expression of CASP9 protein was associated with prognosis and immune cells infiltration of breast cancer. CASP9- naringenin (NGE) is expected to be the most promising candidate gene-compound interaction for the treatment of IBC.

Conclusion: Taken together, CASP9 can be used as a prognostic biomarker and a novel therapeutic target in IBC.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Identification of the DEGs from two IBC microarrays. (a) Venn diagram of 157 overlap DEGs analyzed in two GEO datasets. Volcano plot of gene expression between IBC and non-IBC tissues in GSE45581 (b) and GSE17907 (c). Red dots indicated significantly upregulated genes in IBC; blue dots indicated significantly downregulated genes in IBC; black dots indicated nondifferentially expressed genes. P < 0.05 were considered as significant.
Figure 2
Figure 2
GO and KEGG of DEGs from two microarrays. (a) Sorted by descending order of the number of genes associated with the listed GO ID. (b) Sorted by descending order of −Log10 (P-value) for the GO enrichment terms. (c) KEGG pathway of DEGs expressed in inflammatory breast cancer using the DAVID database.
Figure 3
Figure 3
Module screening and functional analysis of the PPI network. (a) Protein-protein interaction network mapping the differentially expressed genes. (b) Module 1 generating from the PPI network. (c) Module 2 generating from the PPI network. (d) Shows fifteen hub genes with a high degree of connectivity. The red nodes represent upregulated DEGs, while the blue nodes represent downregulated DEGs. DEG: differential expression gene; PPI: protein-protein interaction.
Figure 4
Figure 4
Survival analyses for fifteen hub genes in breast cancer patients. Survival curves show that the expression of PSMC6, AURKB, CASP9, BAD, ZNF24, and SSX2IP was associated with a worse overall survival rate (P < 0.05).
Figure 5
Figure 5
Establishment of gene-compound interaction network. Drug targets of hub genes using the data from CTD and visualized by cytoscape. Red: chemicals; blue: genes.
Figure 6
Figure 6
Correlation of CASP9 expression with immune infiltration level in breast cancer. CASP9 expression is negatively correlated with tumor purity and infiltrating level of B cells and has significant positive correlations with infiltrating levels of CD8+ T cells (r = 0.126, P=7.61e − 05), CD4+ T cells (r = 0.13, P=5.45e − 05), macrophages (r = 0.073, P=2.22e − 02), neutrophils (r = 0.084, P=9.73e − 03), and dendritic cells (r = 0.023, P=4.84e − 01) in breast cancer.
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