Abstract
Thyroid hormones (TH) are multi-functional mediators that fine-tune several physiological processes, including metabolic rate, digestive functions, and tissue development. Thyroid hormone receptors (TRs) are type II nuclear receptors. Thyroid hormone response elements (TRE) of TR promoter regions bind THs to modulate target gene expression at the transcriptional level. Aberrant TR regulation is reported to be correlated with hepatocellular carcinoma (HCC) and disruption of TH signaling is associated with tumorigenesis. Previously, cDNA microarrays were employed to analyze target gene expression following T3 treatment of wild-type TR-expressing hepatoma cells. FOXM1 was consequently identified as a factor negatively regulated by T3 and associated with poor prognosis in several cancer types. Increased FOXM1 expression during late stages of HCC was associated with poor overall and recurrence survival in HCC patients. However, the mechanisms underlying FOXM1 activity in liver cancer progression remain to be elucidated. Here, we showed that TH/TR signaling suppresses FOXM1 mRNA and protein expression. Depletion of FOXM1 inhibited cell growth, migration and invasion rates and induced a decline in oncogenic Cyclin D1, Cyclin E, CDK2, Vimentin, Twist1/2, active-β-catenin, Vimentin and Slug expression. Conversely, overexpression of FOXM1 enhanced cell proliferation, migration and invasion, and expression of oncogenic factors, which was reversed upon FOXM1 depletion. Our collective findings suggest that TH/TR-modulated FOXM1 participates in HCC progression through effects on downstream gene expression.