Cancer Cell Biology
Dkk3, downregulated in cervical cancer, functions as a negative regulator of β-catenin
Article first published online: 11 NOV 2008
Copyright © 2008 Wiley-Liss, Inc.
International Journal of Cancer
Volume 124, Issue 2, pages 287–297, 15 January 2009
How to Cite
Lee, E.-J., Jo, M., Rho, S. B., Park, K., Yoo, Y.-N., Park, J., Chae, M., Zhang, W. and Lee, J.-H. (2009), Dkk3, downregulated in cervical cancer, functions as a negative regulator of β-catenin. Int. J. Cancer, 124: 287–297. doi: 10.1002/ijc.23913
- Issue published online: 14 NOV 2008
- Article first published online: 11 NOV 2008
- Manuscript Accepted: 24 JUL 2008
- Manuscript Received: 17 AUG 2007
- Science Research Center (Molecular Therapy Research Center)
- Korean Science and Engineering Foundation. Grant Number: R11-2000-080-11001-0
- cervical cancer
The Wnt/β-catenin signaling pathway is activated during the malignant transformation of keratinocytes that originate from the human uterine cervix. Dkk1, 2 and 4 have been shown to modulate the Wnt-induced stabilization of the β-catenin signaling pathway. However, the function of Dkk3 in this pathway is unknown. Comparison of the Dkk3 gene expression profiles in cervical cancer and normal cervical tissue by cDNA microarray and subsequent real-time PCR revealed that the Dkk3 gene is frequently downregulated in the cancer. Methylation studies showed that the promoter of Dkk3 was methylated in cervical cancer cell lines and 22 (31.4%) of 70 cervical cancer tissue specimens. This promoter methylation was associated with reduced expression of Dkk3 mRNA in the paired normal and tumor tissue samples. Further, the reintroduction of Dkk3 into HeLa cervical cancer cells resulted in reduced colony formation and retarded cell growth. The forced expression of Dkk3 markedly attenuated β-catenin-responsive luciferase activity in a dose-dependent manner and decreased the β-catenin levels. By utilizing a yeast two-hybrid screen, βTrCP, a negative regulator of β-catenin was identified as a novel Dkk3-interacting partner. Coexpression with βTrCP synergistically enhanced the inhibitory function of Dkk3 on β-catenin. The stable expression of Dkk3 blocks the nuclear translocation of β-catenin, resulting in downregulation of its downstream targets (VEGF and cylcin D), whereas knockdown of Dkk3 abrogates this blocking. We conclude from our finding that Dkk3 is a negative regulator of β-catenin and its downregulation contribute to an activation of the β-catenin signaling pathway. © 2008 Wiley-Liss, Inc.