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Thyroid hormone receptor inhibits hepatoma cell migration through transcriptional activation of Dickkopf 4

Hsiang-Cheng Chi1, Chen-Hsin Liao, Ya-Hui Huang

  • 1Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan 333, Taiwan, ROC.

Biochemical and Biophysical Research Communications
|August 21, 2013
PubMed

Insights

Thyroid hormone (T3) upregulates Dickkopf-4 (DKK4) in liver cancer cells. This T3-induced DKK4 suppresses tumor cell invasion and metastasis by inhibiting Wnt signaling.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Oncology

Background:

  • Triiodothyronine (T3), a thyroid hormone, regulates cellular processes and is implicated in tumor progression.
  • Hypothyroidism is linked to hepatocellular carcinoma (HCC) incidence.
  • Dickkopf-4 (DKK4), a Wnt antagonist, is induced by T3 in HCC cell lines, but the regulatory mechanism is unclear.

Purpose of the Study:

  • To elucidate the mechanism of T3-mediated DKK4 regulation in HCC.
  • To identify the T3 response element (TRE) in the DKK4 promoter.
  • To investigate the functional role of T3-induced DKK4 in HCC progression.

Main Methods:

  • Serial deletion and reporter assays to map the DKK4 promoter.
  • Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) for TRE validation.
  • In vitro and in vivo studies of DKK4 overexpression effects on HCC cell behavior.

Main Results:

  • An atypical direct repeat TRE located between nucleotides -1645 and -1629 was identified in the DKK4 promoter, conferring T3 responsiveness.
  • DKK4 overexpression suppressed HCC cell invasion and metastasis in vitro and in vivo.
  • DKK4 overexpression led to reduced matrix metalloproteinase-2 (MMP-2) expression.

Conclusions:

  • T3 directly upregulates DKK4 expression in HCC via a specific TRE in the promoter region.
  • Upregulated DKK4 antagonizes Wnt signaling, thereby suppressing HCC cell invasion and metastatic potential.
  • These findings reveal a novel molecular mechanism for thyroid hormone action in HCC progression.
Keywords:
DKK4Thyroid hormone receptorTumor suppressor

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