Abstract
Thyroid hormone receptor (TR) mediates the crucial effects of the thyroid hormone (T3) on cellular growth, development, and differentiation. Decreased expression or inactivating somatic mutations of TRs have been found in human cancers of the liver, breast, lung, and thyroid. The mechanisms of TR-associated carcinogenesis are still not clear. To establish the function of TRβ in thyroid cancer cell proliferation, we constructed a recombinant adenovirus vector, AdTRβ, which expresses human TRβ1 cDNA. Thyroid cancer cell lines in which TRβ protein levels were significantly decreased as compared to intact thyroid tissues were infected with AdTRβ and the function of TRβ on cell proliferation and migration was analyzed. Ligand-bound TRβ induced HDAC1 and HDAC3 dissociation from, and histone acetylation associated with the RhoB promoter and enhanced the expression of RhoB mRNA and protein. In AdTRβ-infected cells, T3 and farnesyl transferase inhibitor (FTI)-treatment induced the distribution of RhoB on the cell membrane and enhanced the abundance of active GTP-bound RhoB. This RhoB protein led to p21-associated cell-cycle arrest in the G0/G1 phase, following inhibition of cell proliferation and invasion. Conversely, lowering cellular RhoB by small interfering RNA knockdown in AdTRβ-infected cells led to downregulation of p21 and inhibited cell-cycle arrest. The growth of BHP18-21v tumor xenografts in vivo was significantly inhibited by AdTRβ injection with FTIs-treatment, as compared to control virus-injected tumors. This novel signaling pathway triggered by ligand-bound TRβ provides insight into possible mechanisms of proliferation and invasion of thyroid cancer and may provide new therapeutic targets for thyroid cancers.
Highlights
Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate the actions of the thyroid hormone (T3) in cellular development, growth and differentiation
To explore TRb function in thyroid cancer cell proliferation, we focused on analysis of RhoB, which is a target of TRb and is expressed at very low levels in 130 human cancer cell lines [20]
No TRb protein expression was observed in AdLacz-infected BHP18-21v, FRO or WRO cells or in HepG2 cells that were immunoprecipitated with a mouse monoclonal IgG antibody as a negative control
Summary
Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate the actions of the thyroid hormone (T3) in cellular development, growth and differentiation. Two human TR genes, THRA and THRB that are located on different chromosomes, encode T3-binding isoforms (TRa1, b1, b2, and b3) that are expressed in a tissue- and development-dependent manner [1]. Significant advances have been made in the understanding of TR actions in maintaining normal cellular function. The reduced expression of TRs because of hypermethylation or deletion of TR genes in human cancers suggests that TRs could function as tumor suppressors [2]. A close association of somatic mutations of TRs with thyroid cancers further supports the notion that the loss of normal functions of TR could lead to uncontrolled growth and loss of cell differentiation [3]
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