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Updated: May 21, 2025
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
BAX-mediated ammonia-driven cell death: a novel prognostic and therapeutic target in clear cell renal cell carcinoma
1Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China.
Background:
ccRCC (clear cell renal cell carcinoma) is characterized by metabolic reprogramming and immunosuppression, leading to poor clinical prognosis. In recent years, ammonia-related cell death has attracted increasing attention as a novel mechanism related to tumor progression, but its role in ccRCC has not been clarified.
Methods:
In this study, the Ammonia-related Signature (AS) of ccRCC was constructed by integrating bioinformatics analysis and experimental verification. Multiple independent cohorts including TCGA, PMID 35,440,542 cohort, E-MTAB-1980, and GSE29609 were used to evaluate prognostic accuracy and clinical relevance, and biological functions of key ammonia related genes were explored by cell proliferation, clonal formation, migration, and invasion assays. ScRNA-seq was used to analyze interaction between AS and immune cells in ccRCC.
Results:
The ammonia-related prognostic model demonstrated robust predictive power in multiple datasets. The high AS group of patients with poor prognosis, and the tumor mutation load, immunosuppressive cell infiltration level and immune checkpoint molecular expression were higher. BAX was a key ammonia-related gene closely related to tumor progression, and its knockdown obviously inhibit proliferation, migration and invasion of ccRCC cells. Single-cell analysis confirmed the activation of ammonia-related signaling pathways in the tumor microenvironment, in particular revealing specific interactions between BAX-positive tumor cells and immunosuppressive cell populations.
Conclusion:
The ammonia-related cell death pathway, especially BAX, can be employed as a potential prognostic marker and therapeutic target for ccRCC, providing new ideas for individualized treatment strategies to overcome immunosuppression and improve clinical prognosis.
Insights
Clear cell renal cell carcinoma (ccRCC) prognosis can be improved by targeting ammonia-related cell death pathways. The study identified BAX as a key gene, offering new therapeutic strategies for ccRCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Clear cell renal cell carcinoma (ccRCC) exhibits metabolic reprogramming and immunosuppression, contributing to poor clinical outcomes.
- The role of ammonia-related cell death in ccRCC progression remains largely uncharacterized.
Purpose of the Study:
- To construct and validate an ammonia-related signature (AS) for ccRCC prognosis.
- To explore the biological functions of key ammonia-related genes and their interaction with the tumor immune microenvironment.
Main Methods:
- Bioinformatic analysis and experimental validation were used to develop the AS for ccRCC.
- Prognostic accuracy was assessed across multiple independent patient cohorts.
- Cellular assays (proliferation, migration, invasion) and single-cell RNA sequencing (scRNA-seq) were employed to investigate gene function and immune interactions.
Main Results:
- The developed AS demonstrated robust predictive power for ccRCC prognosis across diverse datasets.
- Patients in the high AS group exhibited poorer prognosis, increased tumor mutation load, and higher levels of immunosuppressive cell infiltration and immune checkpoint molecule expression.
- The gene BAX was identified as a critical ammonia-related gene; its knockdown significantly inhibited ccRCC cell proliferation, migration, and invasion. Single-cell analysis revealed specific interactions between BAX-positive tumor cells and immunosuppressive cells.
Conclusions:
- The ammonia-related cell death pathway, particularly involving BAX, serves as a promising prognostic marker for ccRCC.
- Targeting ammonia-related cell death pathways presents a novel therapeutic strategy for ccRCC, potentially overcoming immunosuppression and improving patient outcomes.
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