Integrative computational and experimental analysis identifies MEK-mediated carcinogenic effects of bisphenol A and...

Area of Science:

• Toxicogenomics
• Machine Learning
• Molecular Biology

Background:

• Endocrine-disrupting chemicals (EDCs) like BPA, DEP, DMP, and DOP are linked to various cancers.
• Nasopharyngeal carcinoma (NPC) and thyroid carcinoma (THCA) are malignancies where EDC involvement requires further investigation.

Purpose of the Study:

• To investigate the carcinogenic effects of BPA, DEP, DMP, and DOP on NPC and THCA.
• To identify shared molecular targets and pathways affected by these EDCs in both cancer types.
• To develop predictive models for cancer diagnosis and prognosis based on EDC-related gene expression.

Main Methods:

• Integrated pipeline combining toxicogenomics, machine learning, molecular docking, and in vitro experiments.
• Intersection analysis of gene expression data to identify common targets in NPC and THCA.
• Machine learning model construction for predicting diagnostic genes.
• Molecular docking simulations to assess EDC-protein binding affinities.
• In vitro assays to evaluate the functional effects of EDCs on cancer cells.

Main Results:

• Identified 19 shared core targets across NPC and THCA, enriched in MAPK, PI3K-AKT, and JAK/STAT pathways.
• Prioritized six diagnostic genes (CCNA2, CDK2, MET, F2, TYMS, PPARG), with high expression of CCNA2, CDK2, MET, and PPARG correlating with worse survival.
• Molecular docking revealed strong binding affinities between BPA/DEP and key proteins like CDK2 and PPARG.
• In vitro studies showed BPA and DEP promote cell proliferation and migration, upregulate oncogenic genes (CDK2, MET, CCNA2), and activate the MEK pathway.

Conclusions:

• BPA and DEP promote head and neck tumor progression, specifically NPC and THCA.
• These effects are mediated through MEK pathway activation and cell-cycle dysregulation.
• The study highlights the potential of identified genes as diagnostic markers and therapeutic targets.