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Published on: July 3, 2013
Integrated Multi-Omics Analysis of 2,3,7,8-TCDD-induced Renal Cell Carcinoma Reveals Core Targets and Mechanistic
Luoping Zheng1, Jiangbin Yang2, Bufang Xiong3
1Department of Urology, Sanming First Hospital Affiliated to Fujian Medical University, Sanming, 365000, Fujian, China.
Background:
TCDD is a long-lasting environmental pollutant. It is also grouped as a substance known to cause cancer in humans (Group 1 carcinogen). However, we do not yet fully understand the exact molecular mechanisms through which TCDD promotes the development of renal cell carcinoma (RCC). Therefore, this study aims to investigate and explain the molecular pathways that connect TCDD exposure to RCC development.
Methods:
We used a combined approach. This approach brought together transcriptomic analysis, network toxicology, weighted gene co-expression network analysis (WGCNA), and machine learning. We used it to explore the relationships between TCDD exposure and RCC. In addition, we applied SHapley Additive exPlanations (SHAP) and molecular docking to assess the binding interactions between TCDD and the key target proteins.
Results:
We found 24 genes that may be involved in TCDD-driven RCC. Then, machine learning analyses selected six genes-PLA2G7, CSRP1, SLC14A1, AOX1, GCNT1, and HPN-as the main regulatory genes. Notably, SHAP analysis showed that PLA2G7 and CSRP1 were the most important contributors. Furthermore, molecular docking simulations showed that TCDD could bind tightly to the proteins made by all six genes.
Discussion:
This study looked at the possible molecular ways that link TCDD exposure to the development of RCC from a systems biology view. SHAP analysis pointed to PLA2G7 and CSRP1 as the main contributing genes. This finding suggests that these molecules could be central hubs in the TCDD-associated regulatory network in RCC. Moreover, lab experiments showed a clear increase in PLA2G7 levels after TCDD exposure. This result points to a possible connection between TCDD exposure and abnormal regulation of PLA2G7.
Conclusion:
Our results suggest that TCDD may help drive the development of RCC through certain signaling pathways and key molecular targets, especially PLA2G7 and CSRP1. These findings give us new possible targets for the treatment of RCC and shine a light on the serious health dangers linked to environmental pollution.
Insights
2,3,7,8-Tetrachlorodibenzodioxin (TCDD) exposure may drive kidney cancer (RCC) by affecting key genes like PLA2G7 and CSRP1. This research uncovers molecular pathways linking environmental pollutants to cancer development.
Area of Science:
- Environmental toxicology
- Molecular oncology
- Systems biology
Background:
- 2,3,7,8-Tetrachlorodibenzodioxin (TCDD) is a persistent environmental pollutant and a known human carcinogen (Group 1).
- The precise molecular mechanisms by which TCDD promotes renal cell carcinoma (RCC) development remain incompletely understood.
- Investigating these mechanisms is crucial for understanding TCDD's carcinogenic potential and developing targeted interventions.
Purpose of the Study:
- To elucidate the molecular pathways connecting TCDD exposure to RCC development.
- To identify key genes and regulatory networks involved in TCDD-induced renal carcinogenesis.
- To provide a systems biology perspective on the molecular underpinnings of TCDD's role in RCC.
Main Methods:
- Integrated transcriptomic analysis, network toxicology, and weighted gene co-expression network analysis (WGCNA).
- Application of machine learning algorithms to identify key regulatory genes from transcriptomic data.
- Utilized SHapley Additive exPlanations (SHAP) and molecular docking to assess gene-protein interactions and TCDD binding affinity.
Main Results:
- Identified 24 candidate genes potentially involved in TCDD-driven RCC.
- Machine learning pinpointed six key regulatory genes: PLA2G7, CSRP1, SLC14A1, AOX1, GCNT1, and HPN.
- SHAP analysis highlighted PLA2G7 and CSRP1 as the most significant contributors, with molecular docking confirming TCDD's strong binding to their respective proteins.
- Experimental validation showed increased PLA2G7 levels following TCDD exposure.
Conclusions:
- TCDD may promote RCC development via specific signaling pathways involving key molecular targets, notably PLA2G7 and CSRP1.
- PLA2G7 and CSRP1 emerge as potential central hubs in the TCDD-associated regulatory network within RCC.
- These findings offer novel therapeutic targets for RCC and underscore the health risks associated with environmental pollution.