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Published on: January 12, 2020
Phthalates unleashed: decoding ovarian carcinogenesis through multi-omics networks, single-cell insights, and
Junchan Yang1, Min Luo1, Hongjun Wang1
1Department of Gynecology, The Eighth Affiliated Hospital, Southern Medical University (The First People's Hospital of Shunde, Foshan), Foshan, 528308, Guangdong, China.
Background:
Despite epidemiological studies linking phthalates to ovarian cancer, their multi-target molecular mechanisms remain unresolved, hindering biomarker discovery and preventive strategies. This study integrates network toxicology, multi-omics analyses, and molecular docking to systematically delineate phthalate-driven oncogenic pathways, thereby bridging mechanistic gaps and informing targeted interventions.
Results:
We identified 234 potential targets related to phthalate exposure and ovarian cancer. Enrichment analysis revealed that these genes are associated with HIF-1 signaling, and metabolic pathways that promote cancer progression. Seven core genes were identified, with six (GAPDH, CASP3, PPARG, ESR1, CYCS, SIRT1, and CCND1) exhibiting differential expression in the TCGA ovarian cancer cohort. Single-cell analysis confirmed their widespread expression across various cell types, underscoring their roles in tumor biology. Molecular docking revealed specific binding interactions between phthalates and six core proteins.
Conclusions:
Integrated computational analyses indicate that phthalates (DEP, DMP, DOP) may drive ovarian carcinogenesis through metabolic reprogramming (HIF-1α/glycolysis), strong binding to SIRT1/PPARα regulators, and tumor microenvironment remodeling. These findings establish a framework for prioritizing environmental carcinogens and identifying exposure biomarkers, with implications for reevaluating phthalate safety and elucidating the SIRT1-HIF1-PPARα axis in cancer pathogenesis.
Insights
Phthalate exposure may drive ovarian cancer by altering cell metabolism and interacting with key regulators like SIRT1 and PPARα. This research identifies potential biomarkers and pathways for targeted interventions against environmental carcinogens.
Area of Science:
- Environmental toxicology
- Molecular oncology
- Computational biology
Background:
- Epidemiological studies suggest a link between phthalate exposure and ovarian cancer.
- The precise molecular mechanisms driving this association remain unclear, impeding biomarker discovery and prevention.
- This study aims to elucidate phthalate-driven oncogenic pathways using integrated computational approaches.
Purpose of the Study:
- To systematically identify molecular targets and pathways involved in phthalate-induced ovarian carcinogenesis.
- To bridge the mechanistic gap between environmental exposure and cancer development.
- To inform the development of targeted interventions and identify potential exposure biomarkers.
Main Methods:
- Network toxicology
- Multi-omics analyses (including gene expression and single-cell data)
- Molecular docking simulations
Main Results:
- Identified 234 potential phthalate targets, enriched in HIF-1 signaling and cancer-promoting metabolic pathways.
- Seven core genes were identified, with six (GAPDH, CASP3, PPARG, ESR1, CYCS, SIRT1, CCND1) differentially expressed in ovarian cancer (TCGA cohort).
- Molecular docking confirmed specific binding interactions between phthalates and six core proteins, suggesting direct molecular interference.
Conclusions:
- Phthalates may promote ovarian cancer via metabolic reprogramming (HIF-1α/glycolysis), binding to SIRT1/PPARα, and remodeling the tumor microenvironment.
- Findings establish a framework for prioritizing environmental carcinogens and identifying exposure biomarkers.
- Highlights the importance of the SIRT1-HIF1-PPARα axis in phthalate-related ovarian cancer pathogenesis and suggests reevaluation of phthalate safety.
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