Metastatic effects of hydroxy-polycyclic aromatic hydrocarbons on liver cancer cells mediated by estrogen receptor α

Hydroxy-polycyclic aromatic hydrocarbons (OH-PAHs) are a growing worldwide concern because of their persistence, ubiquity, and toxicity. Nonetheless, research on the toxicological mechanisms of OH-PAHs remains sparse, particularly concerning the risk of liver cancer. This study evaluated the effects of OH-PAHs on disrupting estrogen receptor alpha (ER alpha) and subsequently facilitating hepatocellular invasion and metastasis. Results revealed that all six OH-PAHs exhibited ER alpha agonistic activities at noncytotoxic levels, which were partially validated using molecular docking (MD) and molecular dynamics simulations (MDS). Furthermore, OH-PAHs with ER alpha agonistic properties stimulated a concentration-dependent increase in the migration and invasion of HepG2 cells. In addition, they disturbed the expression of target genes associated with epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM), and the invasion effects were significantly reversed by adding an ER alpha antagonist. Our results suggest an essential role of ER alpha in the metastasis of liver cancer cells induced by OH-PAHs and emphasize their potential ecological and health hazards.