Dkk3, downregulated in cervical cancer, functions as a negative regulator of β-catenin

Eun Ju Lee, Minwha Jo, Seung Bae Rho, Kyoungsook Park, Yae Na Yoo, Junsoo Park, Myounghee Chae, Wei Zhang, Je Ho Lee

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)287-297
Number of pages11
JournalInternational Journal of Cancer
Volume124
Issue number2
DOIs
Publication statusPublished - 2009 Jan 15

Fingerprint

Catenins
Uterine Cervical Neoplasms
Down-Regulation
Methylation
Vascular Endothelial Growth Factor D
Wnt Signaling Pathway
Oligonucleotide Array Sequence Analysis
Luciferases
Keratinocytes
Transcriptome
Cervix Uteri
Real-Time Polymerase Chain Reaction
Neoplasms
Yeasts
Cell Line
Messenger RNA

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Lee, Eun Ju ; Jo, Minwha ; Rho, Seung Bae ; Park, Kyoungsook ; Yoo, Yae Na ; Park, Junsoo ; Chae, Myounghee ; Zhang, Wei ; Lee, Je Ho. / Dkk3, downregulated in cervical cancer, functions as a negative regulator of β-catenin. In: International Journal of Cancer. 2009 ; Vol. 124, No. 2. pp. 287-297.
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abstract = "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.",
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Lee, EJ, Jo, M, Rho, SB, Park, K, Yoo, YN, Park, J, Chae, M, Zhang, W & Lee, JH 2009, 'Dkk3, downregulated in cervical cancer, functions as a negative regulator of β-catenin', International Journal of Cancer, vol. 124, no. 2, pp. 287-297. https://doi.org/10.1002/ijc.23913

Dkk3, downregulated in cervical cancer, functions as a negative regulator of β-catenin. / Lee, Eun Ju; Jo, Minwha; Rho, Seung Bae; Park, Kyoungsook; Yoo, Yae Na; Park, Junsoo; Chae, Myounghee; Zhang, Wei; Lee, Je Ho.

In: International Journal of Cancer, Vol. 124, No. 2, 15.01.2009, p. 287-297.

Research output: Contribution to journalArticle

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AU - Lee, Eun Ju

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AU - Yoo, Yae Na

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AU - Zhang, Wei

AU - Lee, Je Ho

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