Network toxicological insights into DEHP exposure and thyroid cancer development and progression

Abstract

This study aimed to identify markers of di-2-ethylhexyl phthalate (DEHP) exposure associated with thyroid cancer occurrence and prognosis by integrating network toxicology and molecular docking. Expression profiles and clinical information were obtained from TCGA-THCA and five GEO datasets (GSE3467, GSE3678, GSE33630, GSE53157, and GSE60542). Venn diagram analysis revealed six overlapping genes (CYP1B1, ABCC3, KRT19, CUX2, GABRB2, and TNFSF15) between the combined dataset and DEHP's target genes. GO and KEGG enrichment analyses were conducted on these overlapping genes. Through multivariate COX regression model, it is clearly seen that CYP1B1, GABRB2 and TNFSF15 are highly expressed, and can basically be determined as candidate hub genes. Kaplan-Meier survival analysis indicated that the high-risk group had a significantly poorer prognosis (p < 0.05). Furthermore, prognostic ROC curves based on the GEO validation set demonstrated that CYP1B1, GABRB2, and TNFSF15 were significantly associated with thyroid cancer diagnosis (AUC exceeding 0.86). Finally, molecular docking was employed to visualize the interaction sites between DEHP and its target genes. In conclusion, this study provides novel targets for the prevention and treatment of thyroid cancer in the context of DEHP exposure.

Keywords: DEHP; GEO; TCGA; network toxicological; thyroid cancer.

Figure 1

Visualization of differential genes. (a) Volcanic map of TCGA-THCA (adj.P.Val < 0.05 and |log2(FC)| > 0.2); (b) Heat map of TCGA-THCA; (c) Volcano map from GEO database (adj.P.Val < 0.05 and |log2(FC)| > 1); (d) Heat map of GEO database.

Figure 2

Venn diagram.

Figure 3

String diagram of target gene and enrichment pathway. (a) GO enrichment analysis; (b) KEGG enrichment analysis.

Figure 4

Establishment and evaluation of prognostic model (a) Risk factor map of risk model; (b) Time-dependent ROC curve of TCGA database; (c) KM curve of high and low risk of TCGA database.

Figure 5

(a) The ROC curves of the validation set are GSE3467, GSE3678 and GSE3363 respectively; (b) The ROC curve of the combined validation set. (c) Grouping expression box maps of three key genes; (d) IHC pathological sections of three key genes (DAB staining; 40x; CYP1B1-normol HPA026863, CYP1B1-tumor HPA026863; GABRB2-normol HPA067632, GABRB2-tumor HPA067632; TNFSF15-normol HPA067632, TNFSF15-tumor HPA067632).

Figure 6

The molecular docking models of DEHP with three key proteins, generated using AutoDock 1.5.7 for semi-flexible docking, were visualized utilizing PyMOL.