Thyroid hormone suppresses cell growth by regulating CDK2 and cyclin E1 expression via Hepsin

Thyroid hormone (T3) and its receptor (TR) play crucial roles in regulating cell proliferation and cancer progression, including hepatocellular carcinoma (HCC). However, the specific mechanisms underlying HCC development mediated by T3/TR remain unclear. This study aimed to identify differentially expressed target genes influenced by T3/TR in HCC progression. Microarray profiling analysis revealed hepsin (HPN) as a potential target gene regulated by T3/TR. Quantitative reverse transcription-PCR (qRT-PCR) confirmed that T3/TR upregulates HPN expression. Promoter assays and chromatin immunoprecipitation (ChIP) analysis further demonstrated that TR directly binds to the HPN promoter region (+506/+523), activating its transcription. Functional studies showed that ectopic expression of HPN significantly inhibited cell proliferation. Furthermore, HPN was found to be involved in T3/TR-mediated suppression of cell growth by modulating the expression of CDK2 and cyclin E1. Clinically, HPN expression levels were inversely correlated with CDK2 and cyclin E1 in HCC tissues. These findings establish a novel regulatory relationship among T3/TR, HPN, CDK2, and cyclin E1, highlighting their potential role in controlling liver cancer cell proliferation.