The objective of this study was to identify genes regulated by
thyroid hormone (T(3)) and associated with
tumor invasion. The gene encoding
furin, as previously identified by
cDNA microarray, is known to be up-regulated by T(3) treatment, and stimulated
furin production occurs in thyroidectomized rats after administration of T(3). Presently, by using serial deletion of the promoter and EMSAs, the T(3) response element on the
furin promoter was localized to the -6317/-6302 region. T(3)-mediated
furin up-regulation was cooperative with
TGF-beta because T(3) induction increased after Smad3/4 addition. Furthermore, the invasiveness of HepG2-thyroid
hormone receptor (TR) cells was significantly increased by T(3) treatment, perhaps due to
furin processing of
matrix metalloproteinase-2 and -9. In addition,
furin up-regulation either by stable overexpression or T(3) and/or
TGF-beta induction was evident in severe-combined immune-deficient mice inoculated with HepG2-TRalpha1 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-beta mice was attributed specifically to
furin overexpression in the HepG2-TRalpha1 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, T(3) regulates
furin gene expression via a novel mechanism or in cooperation with
TGF-beta to enhance
tumor metastasis in vitro and in vivo.