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. 2024 Feb 28:17:705-723.
doi: 10.2147/IJGM.S448720. eCollection 2024.

Exploring the Molecular Mechanisms and Shared Gene Signatures Between Systemic Lupus Erythematosus and Bladder Urothelial Carcinoma

Kongjia Wang  1 , Shufei Wang  2 , Yixin Ding  3 , Zengshun Kou  1 , Bo Jiang  1 , Sichuan Hou  1
Affiliations

Exploring the Molecular Mechanisms and Shared Gene Signatures Between Systemic Lupus Erythematosus and Bladder Urothelial Carcinoma

Kongjia Wang et al. Int J Gen Med. .

Abstract

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease associated with increased susceptibility to cancer, including bladder urothelial carcinoma (BLCA). This study investigates the shared molecular mechanisms and gene signatures between SLE and BLCA, shedding light on potential biomarkers and therapeutic targets.

Methods: We compiled gene datasets related to SLE and BLCA from various databases and identified common genes. Differential gene expression analysis, protein-protein interaction networks, and hub gene identification were performed. We studied functional enrichment, immune infiltration, and transcription factor/miRNA regulation networks. We also explored gene-disease interactions and protein-chemical/drug networks. Hub gene expression levels and diagnostic values were validated in TCGA and GEO databases. Prognostic analysis was performed on the core gene MMP9 in the TCGA-BLCA database to study its prognostic value. Finally, the mRNA expression of MMP9 was verified in bladder cancer cell lines and BLCA patient blood. The diagnostic value of MMP9 for BLCA was verified by receiver operating characteristic(ROC) curve analysis of the expression of MMP9 in patients' blood.

Results: We identified 524 common genes between SLE and BLCA, enriched in pathways related to apoptosis and cytokine regulation. Immune infiltration analysis for two diseases. Transcription factors and microRNAs were implicated in regulating these common genes. The gene-disease network linked hub genes with various diseases, emphasizing their roles in autoimmune disease and cancer. Protein-chemical/drug networks highlighted potential treatment options. Finally, our study found that MMP9 is a potential therapeutic target with diagnostic and prognostic value and Immune-related biomarkers in patients with BLCA and SLE.

Conclusion: Our study reveals shared molecular mechanisms, genetic signatures, and immune infiltrates between SLE and BLCA. MMP9 emerges as a potential diagnostic and prognostic biomarker in BLCA, warranting further investigation. These findings provide insights into the pathogenesis of SLE-associated BLCA and may guide future research and therapeutic strategies.

Keywords: MMP9; bladder urothelial carcinoma; gene signatures; immune response; systemic lupus erythematosus.

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Conflict of interest statement

The authors declare no competing interest in this work.

Figures

Figure 1
Figure 1
Workflow diagram of the study.*p<0.05, **p<0.01, ***p<0.001.
Figure 2
Figure 2
Common DEGs of SLE and BLCA are displayed through Venn diagram. (A) Venn diagram of 524 common related genes related to SLE and BLCA. (B) The volcano map of GSE50772. (C) The volcano map of GSE166716. Upregulated genes are marked in red; downregulated genes are marked in blue. (D) Upset map was used to evaluate seven MCODE algorithms (MCC, MNC, Degree, Closeness, Radiality, Stress, and EPC) to select hub genes. (E) Hub genes and their co-expression genes were analyzed via GeneMANIA.
Figure 3
Figure 3
GO and KEGG analyses of 524 common related genes and 16 hub genes. Cell component (CC), Biological process (BP), and Molecular function (MF) of 524 common related genes (B, D, and (F) and 16 hub genes (A, C, and (E). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of 524 common related genes (H) and 16 hub genes (G).
Figure 4
Figure 4
Immune infiltration analysis. The ratio of 22 immune cells in (A) BLCA and (B) SLE samples. (C) The proportion of immune cells in BLCA and control. (D) The proportion of immune cells in SLE and control. Correlations between 16 hub genes and different immune cells in (E) BLCA and (F) SLE samples. (G) The association among immune cells of BLCA. (H) The association among immune cells of SLE. Red color indicates positive correlation; blue color indicates negative correlation.*p<0.05, **p<0.01, ***p<0.001, ****p<0.0001.
Figure 5
Figure 5
TF-gene and Gene-miRNA interaction network analysis. (A) TF-gene interaction network analysis. (B) Gene-miRNA interaction network analysis. Dots represent hub genes; square dots represent miRNAs. Darker colors indicate stronger associations.
Figure 6
Figure 6
Gene-disease, protein-drug and protein-chemical interaction network analysis. (A) Gene-disease interaction network analysis. (B) Protein-drug interaction network analysis. (C) Protein-chemical interaction network analysis. Dots represent hub genes; square dots represent diseases, chemicals, or drugs.
Figure 7
Figure 7
Expression and ROC curves of 16 hub genes in TCGA-BLCA, GSE166716, and GSE50772 databases. Expression of 16 HUB genes in (A) TCGA-BLCA, (B) GSE166716, and (C) GSE50772. ROC curves of 16 HUB genes in (H and I) TCGA-BLCA, (D and E) GSE166716, and (F and G) GSE50772.*p<0.05, **p<0.01, ***p<0.001.
Figure 8
Figure 8
Expression, diagnostic and prognostic value of MMP9 in BLCA. Forest map based on (A) univariate and (B) multivariate Cox analysis for OS. K-M analysis of (C) OS and (D) DSS between MMP9-low and MMP9-high in TCGA-BLCA. (E) A nomogram for predicting 1-, 3-, and 5-year OS survival of BLCA. (F) The calibration curve for the 1-, 3-, and 5-year OS survival nomogram.(G) Expression of MMP9 in SV-HUC-1, T24, J82, and 5637 cell lines. (H) The expression of MMP9 in the blood of BLCA patients and normal people. (I) Diagnostic ROC curves to distinguish BLCA tumor tissues and normal tissues based on the MMP9 expression levels in the blood of BLCA patients and normal people.*p<0.05, **p<0.01, ***p<0.001.
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