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Thyroid Hormone Promotes Cell Invasion through Activation of Furin Expression in Human Hepatoma Cell Lines

Departments of Biochemistry (R.-N.C., Y.-H.H., Y.-C.L., K.-H.L.) and Medicine (C.-T.Y.), School of Medicine, Proteomics Core Laboratory (Y.L.), Chang-Gung University, Taoyuan 333, Taiwan; Liver Research Unit (C.-T.Y.), Chang-Gung Medical Center, Taipei 10591, Taiwan; and Department of Life Sciences (S.-L.C.), National Central University, Jhongli 320, Taiwan, Republic of China

Address all correspondence and requests for reprints to: Dr. Kwang-Huei Lin, Department of Biochemistry, Chang-Gung University, 259 Wen-hwa 1 Road, Taoyuan 333, Taiwan, Republic of China. E-mail: khlin{at}mail.cgu.edu.tw.

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. T₃-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 overexpression or T₃ and/or TGF-β induction was evident in severe-combined immune-deficient mice inoculated with HepG2-TR1 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-TR1 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.