Multi-omics indicating the risk of organochlorines to liver cancer.

Abstract

The incidence and mortality rates of liver cancer remain consistently high worldwide, with China having the highest rates globally. The causes of liver cancer are multifactorial. This study focuses on identifying specific targets that continuously contribute to cellular damage after exposure to environmental organic chlorine compounds (OCCs), ultimately increasing the risk of liver cancer development. Liver cancer-related data were obtained from the GEO and TCGA databases. Differentially expressed genes (DEGs) were analyzed using the "limma" package in R. WGCNA was employed to identify co-expression modules of highly correlated genes in liver cancer. Targets for six representative OCCs-trichloromethane, carbon tetrachloride, PCB28, PCB52, TCDD, and DDT-were retrieved from the PharmGKB, STITCH 4.0, CTD, PharmMapper, and SuperPred databases. Liver cancer-related targets were extracted from the TTD, GeneCards, Digsee, DisGeNET, OMIM, and CTD databases. A "OCCs-key targets-liver cancer" network was constructed using Cytoscape 3.8.1. Core targets were selected through cancer risk prognostic models to further investigate their roles in cancer initiation and progression. GO, KEGG, and disease enrichment analyses were performed using the core targets. The correlation between core targets and 22 types of infiltrating immune cells was analyzed. Molecular docking and dynamics simulations were conducted to verify the binding affinities between OCCs and these core proteins. A total of 195 common targets between OCCs and liver cancer were identified. After performing PPI analysis, 85 key targets were selected to construct a "OCCs-key targets-liver cancer" network. TTK, KPNA2, CDKN3, EZH2, and CPEB3 were identified as core targets through the cancer risk prognostic model. GO enrichment analysis revealed that the core targets were primarily involved in the regulation of the mitotic cell cycle. KEGG enrichment analysis confirmed a strong association between these targets and chemical carcinogenesis, as well as cell cycle regulation. Disease enrichment analysis indicated that the core targets were significantly linked to neoplasms, particularly liver cancer. Immunoinfiltration analysis suggested that tumors may promote immune evasion by increasing the expression of immunosuppressive cells while decreasing the levels of activated immune cells. Molecular docking and dynamics simulations identified key binding interactions, amino acid residues, and binding energies, further confirming strong binding affinities between OCCs and the core targets. This study integrates network toxicology, machine learning, WGCNA, molecular docking, molecular dynamics simulations, and immunoinfiltration analysis, providing evidence that prolonged exposure to OCCs may increase the risk of liver cancer development.

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