title: Thyroid hormone promotes cell invasion through activation of furin expression in human hepatoma cell lines.
abstract: 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.
authors.affiliation: Department of Biochemistry, Chang-Gung University, 259 Wen-hwa 1 Road, Taoyuan 333, Taiwan, Republic of China.
authors.forename: Ruey-Nan
authors.initials: RN
authors.lastname: Chen
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Huang
authors.forename: Ya-Chu
authors.initials: YC
authors.lastname: Lin
authors.forename: Chau-Ting
authors.initials: CT
authors.lastname: Yeh
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.forename: Shen-Liang
authors.initials: SL
authors.lastname: Chen
authors.forename: Kwang-Huei
authors.initials: KH
authors.lastname: Lin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D045683:Furin / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D051381:Rats; D017207:Rats, Sprague-Dawley; D011988:Receptors, Thyroid Hormone / Q000502:physiology; D013963:Thyroid Hormones / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D016212:Transforming Growth Factor beta; C468731:FURIN protein, human; D045683:Furin