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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
Ochratoxin A and Clear Cell Renal Cell Carcinoma: Exploring Potential Molecular Links Through Network Toxicology and
Chenjie Huang1, Lulu Wei1, Wenqi Yuan1
1School of Clinical Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China.
Abstract:
Ochratoxin A (OTA), a prevalent food contaminant, is closely linked to the development of various cancers, including clear cell renal cell carcinoma (ccRCC). However, the potential mechanisms remain to be explored. In this study, we employed network toxicology, machine learning, and molecular docking techniques to systematically investigate the potential molecular mechanisms underlying OTA-associated ccRCC. We normalized transcriptional data from two Gene Expression Omnibus (GEO) datasets and analyzed it using differential expression analysis and weighted gene co-expression network analysis (WGCNA), identifying 3224 ccRCC-associated target genes. These were intersected with 232 predicted OTA target genes, yielding a total of 56 overlapping targets. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that these targets were primarily enriched in critical biological processes, including extracellular matrix remodeling, immune microenvironment regulation, signaling pathway transduction, cellular metabolism, and protein homeostasis. Machine learning analysis identified "glmBoost + RF" (a sequential combination of feature selection and classifier) as the optimal model, from which nine key genes were extracted. SHapley Additive exPlanations (SHAP) analysis revealed five core genes (IGFBP3, ITGA5, PYGL, SLC22A8, LTB4R), with IGFBP3 and ITGA5 serving as the principal driver genes of the model. Validation of the model's diagnostic efficacy and single-cell transcriptome analysis indicated that the core genes exhibited significant differential expression patterns, cell-type-specific expression characteristics, and high independent diagnostic efficacy. Molecular docking analyses predicted stable interactions between OTA and the core target proteins. These findings suggest potential molecular links between OTA exposure and ccRCC, providing a foundation for hypothesis generation and future experimental validation.
Insights
Ochratoxin A (OTA) exposure may drive clear cell renal cell carcinoma (ccRCC) through specific molecular pathways. This study identified key genes like IGFBP3 and ITGA5 involved in OTA-induced ccRCC development.
Area of Science:
- Toxicology and Oncology
- Bioinformatics and Computational Biology
Background:
- Ochratoxin A (OTA) is a common food contaminant linked to clear cell renal cell carcinoma (ccRCC).
- The precise molecular mechanisms connecting OTA exposure to ccRCC remain largely unelucidated.
Purpose of the Study:
- To systematically investigate the molecular mechanisms underlying OTA-associated ccRCC using integrated network toxicology, machine learning, and molecular docking.
- To identify key genes and pathways involved in the pathogenesis of ccRCC induced by OTA.
Main Methods:
- Utilized Gene Expression Omnibus (GEO) datasets for differential expression and weighted gene co-expression network analysis (WGCNA).
- Integrated network toxicology, machine learning (glmBoost + RF, SHAP), and molecular docking.
- Performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses.
Main Results:
- Identified 56 overlapping genes between ccRCC and OTA targets, enriched in extracellular matrix remodeling, immune microenvironment, and metabolism.
- Extracted nine key genes, with IGFBP3 and ITGA5 identified as principal drivers using SHAP analysis.
- Validated core genes' differential expression, cell-type specificity, and diagnostic efficacy; predicted stable OTA-protein interactions.
Conclusions:
- Established potential molecular links between OTA exposure and ccRCC pathogenesis.
- Highlighted IGFBP3 and ITGA5 as critical drivers in OTA-induced ccRCC.
- Provided a basis for future experimental validation and therapeutic strategies.
