Regulatory Role of the Clock Gene Nr1d1 in Oxygenated Polycyclic Aromatic Hydrocarbons 9-Fluorenone Induced Tumorigenesis
Oxygenated polycyclic aromatic hydrocarbons (OPAHs) are prevalent environmental contaminants with high toxicity and demonstrated tumor-promoting effects. Circadian clock genes are critical regulators of cellular homeostasis and tumorigenesis. This study investigated the role of clock genes in OPAH-induced tumor promotion using 9-fluorenone (FLO), a dominant OPAH. Human hepatocellular carcinoma (HepG2) cells were exposed to 0, 10, and 30 μmol·L−1 FLO. Cell proliferation was assessed via colony formation and EdU staining, and mRNA expression of core clock genes (Bmal1, Npas2, Nr1d1, Per2, Cry1, Dbp) was quantified by RT-qPCR. Results demonstrated that FLO exposure significantly enhanced cell proliferation and dose-dependently suppressed Nr1d1 expression. In synchronized cells, FLO dampened the amplitude of Nr1d1 mRNA oscillation. Pretreatment with SR9009, a selective Nr1d1 agonist, effectively inhibited FLO-induced proliferation. These findings indicate that Nr1d1 plays a pivotal role in the tumorigenic cascade initiated by polycyclic aromatic hydrocarbon derivatives, providing mechanistic insights into OPAH health impacts and potential intervention strategies.