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Identification of SERPINE1, LOX, and TGFB1 as Potential Therapeutic Targets in Oral Squamous Cell Carcinoma
Guosheng Sun1, Dezhi Shen2, Meng Hou1
1School of Stomatology, Jining Medical University, Jining, 272002, China.
Introduction:
We integrated bulk and single-cell transcriptomics and machine learning to dissect HIF1A-driven signaling in the Tumor Microenvironment (TME) of Oral Squamous Cell Carcinoma (OSCC) and identified actionable therapeutic targets.
Methods:
The data from bulk and single-cell RNA sequencing were used to characterize HIF1A activity, followed by GSEA, DEG, and PPI network analyses. Hub genes were then identified using two machine learning algorithms, and their cell-specific expressions were determined. Molecular docking was used to reveal potential drug-target interactions. in vitro cell functional experiments, including Cell Counting kit-8 (CCK-8) assay, wound healing assay, and Transwell assay, were performed to verify the biological role of the biomarkers, particularly SERPINE1, in OSCC.
Results:
GSEA confirmed robust HIF1A signaling activation in OSCC. A total of 48 overlapping DEGs and HIF1A-related genes were initially identified and then reduced to 7 hub genes. Among them, SERPINE1, LOX, and TGFB1 were consistently identified by two machine learning algorithms. in vitro experiments confirmed that the expression of SERPINE1, LOX, and TGFB1 was significantly upregulated in OSCC. Moreover, silencing of SERPINE1 markedly reduced the viability, migration, and invasion of OSCC cells. Functional analyses indicated that these genes drive hypoxia, angiogenesis, and Epithelial-Mesenchymal Transition (EMT). Molecular docking identified ciglitazone as a potential dual inhibitor of SERPINE1 and TGFB1.
Discussion:
The current study revealed HIF1A-associated signaling in OSCC and identified three key genes related to the HIF1A pathway. However, these results were obtained based on public datasets and predictive modeling, requiring further experimental validation.
Conclusion:
A hypoxia-associated gene model was identified for OSCC, and these genes were expressed in distinct TME cell types. These findings highlighted the potential of drug repurposing to target multicellular hypoxic signaling in OSCC.
Insights
This study reveals key genes driving Oral Squamous Cell Carcinoma (OSCC) through HIF1A signaling in the tumor microenvironment. These findings identify potential therapeutic targets and drug repurposing opportunities for OSCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Oral Squamous Cell Carcinoma (OSCC) is a prevalent cancer with complex tumor microenvironment (TME) signaling.
- Hypoxia-Inducible Factor 1-Alpha (HIF1A) plays a critical role in OSCC progression and TME modulation.
- Understanding HIF1A-driven signaling is crucial for identifying novel therapeutic strategies.
Purpose of the Study:
- To dissect HIF1A-driven signaling pathways within the OSCC TME.
- To identify actionable therapeutic targets and biomarkers associated with HIF1A activity.
- To explore potential drug repurposing for targeting multicellular hypoxic signaling in OSCC.
Main Methods:
- Integrated bulk and single-cell transcriptomics with machine learning algorithms.
- Performed Gene Set Enrichment Analysis (GSEA), Differential Gene Expression (DEG), and Protein-Protein Interaction (PPI) network analyses.
- Utilized in vitro functional assays (CCK-8, wound healing, Transwell) and molecular docking to validate findings and predict drug-target interactions.
Main Results:
- Confirmed robust HIF1A signaling activation in OSCC, identifying 7 hub genes including SERPINE1, LOX, and TGFB1.
- Demonstrated significant upregulation of SERPINE1, LOX, and TGFB1 in OSCC cells.
- Showcased that SERPINE1 silencing reduced OSCC cell viability, migration, and invasion, highlighting its role in hypoxia, angiogenesis, and Epithelial-Mesenchymal Transition (EMT).
Conclusions:
- Identified a hypoxia-associated gene model for OSCC with distinct TME cell type expression.
- Highlighted SERPINE1, LOX, and TGFB1 as key genes involved in HIF1A-driven OSCC progression.
- Suggested potential for drug repurposing, with ciglitazone identified as a potential dual inhibitor of SERPINE1 and TGFB1.
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