Elucidating the correlation between polychlorinated dibenzo-p-dioxins and prostate cancer progression: Insights from gene expression and molecular docking.

[OBJECTIVE] Polychlorinated dibenzo-p-dioxins (PCDDs) present a significant long-term threat to human health attributable to their toxicological properties, chemical stability and propensity for bioaccumulation. This study seeks to explore the correlation between PCDDs exposure and prostate cancer (PCa) through comprehensive analysis.

[METHODS] The multi-dimensional analysis was conducted based on various online databases. Functional enrichment analysis clarified the biological functions of PCDDs-related genes (PRGs). Furthermore, PRGs were employed in the construction of a novel prognostic model. The validity of this model was evaluated through both internal and external validation processes. Molecular docking was performed to evaluate the binding capacity of PCDDs to crucial proteins. Finally, in vitro and in vivo assays were conducted to examine the biological roles and underlying mechanisms of PCDDs in PCa progression.

[RESULTS] A total of 217 PRGs with differential expression were screened based on the CTD and TCGA database. The GO and KEGG enrichment analyses indicated that these genes were mainly involved in pathways related to cell motility, fatty acid metabolic process and the Hippo signaling pathway. In addition, a novel PCDDs-related prognostic model was developed. Patients with high-risk scores had significantly shorter biochemical recurrence-free survival than those with low-risk scores across the training, test, entire TCGA, and GEO cohorts. The AUCs at 5 years were 0.736, 0.720, 0.731 and 0.677 in the four cohorts sequentially. A practical nomogram was presented for potential clinical application. The anti-cancer drug sensitivity analysis examined the potential therapeutic compounds for patients with different risk scores. The molecular docking analysis revealed the binding capacity of OCDD to crucial proteins. The EdU assay revealed that OCDD effectively enhanced the proliferation of PCa cells. Furthermore, transwell and wound healing assays demonstrated that OCDD treatment significantly increased the migratory and invasive capabilities of PCa cells. In vivo studies using nude mice xenograft models showed a marked enhancement in prostate tumor growth as a result of OCDD treatment. Finally, western blot and immunofluorescence analyses revealed that OCDD treatment could exert an inhibitory effect on the Hippo signaling pathway.

[CONCLUSIONS] This study provided several novel insights into the role of PCDDs in PCa, along with an enhanced understanding of the association between environmental toxicants and cancer progression.