Thyroid hormone promotes cell invasion through activation of furin expression in human hepatoma cell lines

The objective of this study was to identify genes regulated by thyroid hormone (T₃) and associated with tumor invasion. The gene encoding furin, as previously identified by cDNA microarray, is known to be up-regulated by T₃ treatment, and stimulated furin production occurs in thyroidectomized rats after administration of T₃. Presently, by using serial deletion of the promoter and EMSAs, the T₃ response element on the furin promoter was localized to the -6317/-6302 region. T ₃-mediated furin up-regulation was cooperative with TGF-β because T₃ induction increased after Smad3/4 addition. Furthermore, the invasiveness of HepG2-thyroid hormone receptor (TR) cells was significantly increased by T₃ treatment, perhaps due to furin processing of matrix metalloproteinase-2 and -9. In addition, furin up-regulation either by stable over-expression or T₃ and/or TGF-β induction was evident in severe-combined immune-deficient mice inoculated with HepG2-TRα1 cells. The HepG2-furin mice displayed a higher metastasis index and tumor size than HepG2-neo mice. Notably, the increased liver and lung tumor number or size in the hyperthyroid severe-combined immune-deficient mice as well as TGF-β mice was attributed specifically to furin overexpression in the HepG2-TRα1 cells. Furthermore, this study demonstrated that furin overexpression in some types of hepatocellular carcinomas is TR dependent and might play a crucial role in the development of hepatocellular carcinoma. Thus, T₃ regulates furin gene expression via a novel mechanism or in cooperation with TGF-β to enhance tumor metastasis in vitro and in vivo.