title: Thyroid hormone receptor inhibits hepatoma cell migration through transcriptional activation of Dickkopf 4.
abstract: Triiodothyronine (T3) is a potent form of thyroid hormone mediates several physiological processes including cellular growth, development, and differentiation via binding to the nuclear thyroid hormone receptor (TR). Recent studies have demonstrated critical roles of T3/TR in tumor progression. Moreover, long-term hypothyroidism appears to be associated with the incidence of human hepatocellular carcinoma (HCC), independent of other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein that antagonizes the canonical Wnt signaling pathway, is induced by T3 at both mRNA and protein levels in HCC cell lines. However, the mechanism underlying T3-mediated regulation of DKK4 remains unknown. In the present study, the 5' promoter region of DKK4 was serially deleted, and the reporter assay performed to localize the T3 response element (TRE). Consequently, we identified an atypical direct repeat TRE between nucleotides -1645 and -1629 conferring T3 responsiveness to the DKK4 gene. This region was further validated using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA). Stable DKK4 overexpression in SK-Hep-1 cells suppressed cell invasion and metastatic potential, both in vivo andin vitro, via reduction of matrix metalloproteinase-2 (MMP-2) expression. Our findings collectively suggest that DKK4 upregulated by T3/TR antagonizes the Wnt signal pathway to suppress tumor cell progression, thus providing new insights into the molecular mechanism underlying thyroid hormone activity in HCC.
authors: Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan, ROC.
authors: Hsiang-Cheng
authors: HC
authors: Chi
authors: Chen-Hsin
authors: CH
authors: Liao
authors: Ya-Hui
authors: YH
authors: Huang
authors: Sheng-Ming
authors: SM
authors: Wu
authors: Chung-Ying
authors: CY
authors: Tsai
authors: Chia-Jung
authors: CJ
authors: Liao
authors: Yi-Hsin
authors: YH
authors: Tseng
authors: Yang-Hsiang
authors: YH
authors: Lin
authors: Cheng-Yi
authors: CY
authors: Chen
authors: I-Hsiao
authors: IH
authors: Chung
authors: Tzu-I
authors: TI
authors: Wu
authors: Wei-Jan
authors: WJ
authors: Chen
authors: Kwang-Huei
authors: KH
authors: Lin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D002465:Cell Movement; D018450:Disease Progression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D015533:Transcriptional Activation; D014284:Triiodothyronine / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: C442333:DKK4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D020778:Matrix Metalloproteinase 2
keywords: DKK4; Thyroid hormone receptor; Tumor suppressor