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Integrating network toxicology, machine learning, and experimental evidence reveals candidate targets and pathways in
Hanxiao Shen1, Wei Zhu2, Ding Wang1
1Institute of Pharmaceutical Innovation, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China.
Abstract:
Previous studies have suggested that exposure to carcinogenic polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) pollutants may increase the risk of colon cancer, their underlying molecular mechanisms remain unclear. In this study, we employed a multidisciplinary approach integrating network toxicology, machine learning, molecular docking, molecular dynamics (MD) simulations and in vivo experiments to investigate how PCDD/Fs may promote colon carcinogenesis. Machine learning algorithms converged on MMP7 as a core target, MMP7 expression was upregulated in colon cancer tissues and was associated with immune cell infiltration. Molecular docking and MD simulations further suggested stable interactions between the five representative PCDD/F congeners and the target proteins (MMP7, SRC, and HSP90AA1), supporting their potential involvement in disease progression. Consistent with these in silico findings, exposure of mice to 24 μg/kg TCDF significantly increased the expression of Mmp7 and Hsp90aa1 in murine colonic tissues, increased the levels of proinflammatory cytokines Ifn-γ, Il-1β, and Il-6, and downregulated the expression of Mucin 2 (MUC2). Connectivity Map analysis based on the PCDD/F-related gene signature identified five candidate compounds targeting MMP7 and HSP90AA1, of which four HSP90 inhibitors (tanespimycin, alvespimycin, NVP-AUY922 and AT-13387) showed negative connectivity scores, suggesting potential to reverse the pollutant-induced expression profile.
Insights
Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) may increase colon cancer risk. This study reveals molecular mechanisms involving MMP7 and identifies potential therapeutic HSP90 inhibitors to reverse pollutant effects.
Area of Science:
- Environmental Toxicology
- Molecular Biology
- Computational Biology
Background:
- Carcinogenic polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) are linked to increased colon cancer risk.
- The precise molecular mechanisms driving PCDD/F-induced colon carcinogenesis are not fully understood.
Purpose of the Study:
- To elucidate the molecular pathways through which PCDD/Fs promote colon cancer.
- To identify potential therapeutic targets and compounds for mitigating PCDD/F-related colon carcinogenesis.
Main Methods:
- Integrated network toxicology, machine learning, molecular docking, and molecular dynamics (MD) simulations.
- In vivo mouse models were used to validate in silico findings.
- Connectivity Map analysis was employed to identify potential therapeutic agents.
Main Results:
- Machine learning identified MMP7 as a key target, upregulated in colon cancer and associated with immune infiltration.
- Stable interactions were predicted between PCDD/F congeners and target proteins (MMP7, SRC, HSP90AA1).
- In vivo TCDF exposure increased Mmp7, Hsp90aa1, and pro-inflammatory cytokines, while decreasing MUC2 expression in mice.
Conclusions:
- PCDD/Fs promote colon carcinogenesis through specific molecular interactions and altered gene expression.
- MMP7 and HSP90AA1 are identified as critical targets in PCDD/F-induced colon cancer.
- Four HSP90 inhibitors demonstrate potential for reversing PCDD/F-induced molecular changes, offering therapeutic avenues.
