Network toxicology and molecular docking identify BRCA1 as a functional target of the dietary carcinogen PhIP in colorectal cancer.

objectiveTo clarify the molecular mechanism of PhIP-induced colorectal cancer and identify the potential of core regulatory targets as biomarkers for colorectal cancer.

methodsThe chemical structure of PhIP was obtained through the PubChem database and ProTox-3.0 platform, and its physicochemical properties and toxic effects were clarified. PhIP action targets were screened from the ChEMBL, STITCH, and SwissTargetPrediction databases, and pathogenic targets for colorectal cancer were acquired from the GeneCards, OMIM, and TTD databases. Intersection targets of PhIP and colorectal cancer were further screened. A compound-target regulatory network was constructed and subjected to functional enrichment analysis and PPI analysis. Core targets were further identified via CytoHubba, their expression differences in colorectal cancer were clarified, and their diagnostic efficacy and prognostic value were evaluated using ROC curves and Kaplan-Meier survival curves. Subsequently, the expression of core targets was validated through immunohistochemistry and immunofluorescence, and immune infiltration analysis was performed to clarify their correlation with immune cells. Finally, the interaction mechanism between PhIP and core targets was revealed at the molecular structural level through molecular docking technology.

resultsA total of 1088 PhIP action targets and 281 colorectal cancer-associated targets were screened, containing 35 intersection targets. Functional enrichment analysis found that these intersection targets were associated with biological processes or signaling pathways such as protein phosphorylation, regulation of cell cycle process, pathways in cancer, and estrogen signaling pathway. Target proteins like BRCA1, ESR1, and BCL2 were located at the center of the PPI network, and BRCA1 was identified as the core regulatory target based on Degree value. Expression difference analysis and immunohistochemistry results showed that BRCA1 was significantly highly expressed in colorectal cancer and had good diagnostic efficacy and prognostic value. Immune infiltration results indicated that BRCA1 was closely related to immune cells such as Th2 cells, T helper cells, Tcm, and iDC. Simultaneously, the gene mutation landscape suggested that mutations in genes like APC and TP53 also participated in colorectal cancer development. Finally, molecular docking results indicated strong binding activity between PhIP and BRCA1.

conclusionPhIP acts on the core target BRCA1 and participates in colorectal cancer development through mechanisms affecting immune cells, gene mutations, etc. BRCA1 has good diagnostic efficacy and prognostic value in colorectal cancer and is expected to become a new diagnostic and prognostic target for colorectal cancer.