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Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis
Peize Yu1,2, Qikai Zhong1,2, Xinlei Wang1,3
1Department of Urology, Xuzhou Medical University, Xuzhou, Jiangsu, China.
Background:
Clear cell renal cell carcinoma (KIRC) is the most aggressive renal carcinoma subtype of renal carcinoma, characterized by high mortality, early metastasis, and resistance to treatment. Ammonia-induced cell death (AICD) has recently been identified as a novel metabolic mechanism influencing tumor progression, yet its prognostic implication and regulatory networks in KIRC remain underexplored.
Methods:
Transcriptomic and clinical information from the TCGA-KIRC cohort and the validation cohort (E-MTAB-1980) were analyzed. Differentially expressed AICD-related genes were identified through differential expression analysis, univariate Cox regression, and machine learning algorithms (LASSO, random forest, and CoxBoost). A prognostic risk model was developed via multivariate Cox regression. Spatial and single-cell transcriptomics were employed to characterize the immune microenvironment heterogeneity. Cell-based experiments were performed to investigate the potential involvement of ATP1A1 in KIRC. Molecular docking and pan-cancer analyses were conducted to identify therapeutic candidates and ATP1A1-related mechanisms.
Results:
Five AICD-related genes (FOXM1, ANK3, ATP1A1, HADH, and PLG) were identified and selected to construct a risk score model. The model demonstrated high accuracy and was integrated into a nomogram for clinical application. High-risk (HR) patients exhibited immunosuppressive microenvironments, elevated tumor mutational burden (TMB), and genomic instability. In vitro functional assays confirmed that ATP1A1 knockdown significantly enhanced the proliferative, migratory, and invasive capabilities of renal carcinoma cells (A498 and 786-O), suggesting a suppressive role for ATP1A1 in malignant tumor progression. ATP1A1, a core gene, was associated with metabolic reprogramming and chemotherapy sensitivity across multiple cancers. Molecular docking revealed Emodinanthrone as a high-affinity ligand for ATP1A1 (-6.8 kcal/mol).
Conclusion:
This study identifies an AICD-associated gene signature as a robust prognostic tool for KIRC, revealing its interactions with immune evasion and genomic instability. ATP1A1 is proposed as a promising therapeutic target, with Emodinanthrone emerging as a novel drug candidate. These findings contribute to the advancement of personalized treatment strategies for KIRC patients.
Insights
This study identifies a novel gene signature linked to ammonia-induced cell death (AICD) for predicting clear cell renal cell carcinoma (KIRC) outcomes. ATP1A1 is a potential therapeutic target, with Emodinanthrone showing promise as a drug candidate.
Area of Science:
- Oncology
- Metabolic pathways
- Genomics
Background:
- Clear cell renal cell carcinoma (KIRC) is an aggressive cancer with poor prognosis.
- Ammonia-induced cell death (AICD) is a metabolic mechanism impacting tumor progression, but its role in KIRC is unclear.
Purpose of the Study:
- To explore the prognostic significance and regulatory networks of AICD in KIRC.
- To develop a risk model for KIRC prognosis based on AICD-related genes.
- To investigate ATP1A1 as a potential therapeutic target.
Main Methods:
- Analysis of TCGA-KIRC and E-MTAB-1980 transcriptomic and clinical data.
- Identification of differentially expressed AICD genes using machine learning algorithms.
- Development of a prognostic risk model via multivariate Cox regression.
- Characterization of the tumor immune microenvironment using spatial and single-cell transcriptomics.
- In vitro experiments and molecular docking to validate ATP1A1 function and identify drug candidates.
Main Results:
- A five-gene AICD signature (FOXM1, ANK3, ATP1A1, HADH, PLG) was developed, accurately predicting KIRC patient prognosis.
- High-risk patients displayed immunosuppressive microenvironments, elevated tumor mutational burden, and genomic instability.
- ATP1A1 knockdown enhanced KIRC cell proliferation, migration, and invasion, indicating a tumor-suppressive role.
- ATP1A1 is linked to metabolic reprogramming and chemotherapy sensitivity across cancers.
- Emodinanthrone was identified as a high-affinity ligand for ATP1A1.
Conclusions:
- An AICD-associated gene signature serves as a robust prognostic tool for KIRC, correlating with immune evasion and genomic instability.
- ATP1A1 is a promising therapeutic target for KIRC, with Emodinanthrone as a potential novel drug candidate.
- These findings support the development of personalized treatment strategies for KIRC.
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