These authors contributed equally to this work.
Article first published online: 13 JAN 2012
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 3, pages 910–920, March 2012
How to Cite
Liao, C.-H., Yeh, C.-T., Huang, Y.-H., Wu, S.-M., Chi, H.-C., Tsai, M.-M., Tsai, C.-Y., Liao, C.-J., Tseng, Y.-H., Lin, Y.-H., Chen, C.-Y., Chung, I.-H., Cheng, W.-L., Chen, W.-J. and Lin, K.-H. (2012), Dickkopf 4 positively regulated by the thyroid hormone receptor suppresses cell invasion in human hepatoma cells. Hepatology, 55: 910–920. doi: 10.1002/hep.24740
Potential conflict of interest: Nothing to report.
Supported by grants from Chang-Gung University, Taoyuan, Taiwan (CMRPD 34013, NMRP 140511) and from the National Science Council of the Republic of China (NSC 94-2320-B-182-052).
- Issue published online: 23 FEB 2012
- Article first published online: 13 JAN 2012
- Accepted manuscript online: 12 OCT 2011 12:50PM EST
- Manuscript Accepted: 27 SEP 2011
- Manuscript Received: 27 JAN 2011
Thyroid hormone (T3) mediates cellular growth, development, and differentiation by binding to the nuclear thyroid hormone receptor (TR). Recent studies suggest that long-term hypothyroidism is associated with human hepatocellular carcinoma (HCC) independent from other major HCC risk factors. Dickkopf (DKK) 4, a secreted protein, antagonizes the Wnt signal pathway. In this study, we demonstrate that T3 may play a suppressor role by inducing DKK4 expression in HCC cells at both the messenger RNA (mRNA) and protein levels. DKK4 was down-regulated in 67.5% of HCC cancerous tissues. The decrease in DKK4 levels was accompanied by a concomitant decrease in TR protein levels in the matched cancerous tissues in 31% of tissues compared by immunoblotting with the adjacent noncancerous tissues. Further, TR and DKK4 expression levels were positively correlated in both normal and cancerous specimens by tissue array analysis. In function assays, stable DKK4 transfected into J7 or HepG2 cells decreased cell invasion in vitro. Conversely, knocking down DKK4 restores cell invasiveness. DKK4-expressing J7 clones showed increased degradation of β-catenin, but down-regulation of CD44, cyclin D1, and c-Jun. To investigate the effect of DKK4 and TR on tumor growth in vivo, we established a xenograft of J7 cells in nude mice. J7-DKK4 and J7-TRα1 overexpressing mice, which displayed growth arrest, lower lung colony formation index, and smaller tumor size than in control mice, supporting an inhibitory role of DKK4 in tumor progression. Conclusion: Taken together, these data suggest that the TR/DKK4/Wnt/β-catenin cascade influences the proliferation and migration of hepatoma cells during the metastasis process and support a tumor suppressor role of the TR. (Hepatology 2012)