Development of a Mitochondrial Permeability Transition‐Driven Necrosis‐Related Prognostic Signature in Cervical Cancer: Integrating Bulk Transcriptomic and Single‐Cell Data
ABSTRACT Background Cervical cancer (CC) is a prevalent gynecological malignancy with notable heterogeneity. The role of mitochondrial permeability transition (MPT)‐driven necrosis, a form of cell death due to mitochondrial dysfunction, in CC progression and prognosis is poorly understood and repres...
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| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-08-01
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| Series: | Cancer Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cam4.71094 |
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| Summary: | ABSTRACT Background Cervical cancer (CC) is a prevalent gynecological malignancy with notable heterogeneity. The role of mitochondrial permeability transition (MPT)‐driven necrosis, a form of cell death due to mitochondrial dysfunction, in CC progression and prognosis is poorly understood and represents a promising therapeutic target for cancers. This study aimed to create a new prognostic signature linked to MPT‐driven necrosis, improving CC prediction and prognosis. Methods This study utilized the GSE63514, TCGA‐CESC, CGCI‐HTMCP‐CC, and GSE197641 transcriptome datasets. Firstly, the GSE63514 dataset was utilized to identify differentially expressed genes (DEGs). Differentially expressed MPT‐driven necrosis‐related genes (DE‐MRGs) were obtained by intersecting DEGs with MRGs. Regression analyses were performed to identify genes significantly associated with prognosis. A prognostic model was established in TCGA‐CESC, followed by independent validation and nomogram construction. Additional analyses included immune infiltration, enrichment analysis, and drug susceptibility based on high‐ and low‐risk groups. Finally, cell communication analysis was performed to investigate interactions between key cell types. Results A total of 156 DE‐MRGs were identified. Regression analyses identified three prognostic genes (ICOS, MMP3, and POSTN) to construct a prognostic risk signature. Then, risk score was an independent prognostic factor for CC, and a nomogram demonstrated effective predictive accuracy for CC survival outcomes. The risk signature was linked to immune‐associated processes such “Antigen processing and presentation” and immune cell infiltration, especially M0 macrophages and CD8 T cells. Cell communication analysis uncovered a strong interaction between endothelial cells and monocytes. To validate the molecular mechanisms, qRT‐PCR, cell proliferation, and wound healing assays were performed. Functional tests showed that MMP3 and POSTN knockdown drastically reduced CC cell growth and migration. Conclusion This study developed a novel prognostic risk signature based on ICOS, MMP3, and POSTN. MMP3 and POSTN knockdown significantly decrease CC cell growth and migration, highlighting their potential as therapeutic targets. |
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| ISSN: | 2045-7634 |