SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway

Ming Tzeung Chung, Hung Cheng Lai, Huey Kang Sytwu, Ming D. Yan, Yu Lueng Shih, Cheng Chang Chang, Mu Hsien Yu, Hang Seng Liu, Da W. Chu, Ya W. Lin

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Objectives: Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cancers, including cervical cancer. The secreted frizzled-related proteins (SFRPs) function as Wnt antagonists and play important implications in carcinogenesis. Recently, we have shown that SFRP1 and SFRP2 are frequently downregulated through promoter hypermethylation. However, the function of SFRP1 and SFRP2 in cervical cancer remains unclear. Methods: To improve our understanding of the role of SFRP1 and SFRP2 in cervical cancer cells, we use overexpression or shRNA approach in cervical cancer cell lines. Results: Restoration of the expression of SFRP1 and SFRP2 attenuated Wnt signaling in CaSki cells, decreased abnormal accumulation of free β-catenin in the nucleus, and suppressed cancer cell growth. In addition, different statuses of β-catenin accumulation in the cytoplasm of CaSki or HeLa3rd cells were observed, suggesting that different Wnt pathways are executed. Furthermore, we demonstrated that SFRP1 and SFRP2 enhance the expression of the epithelial marker E-cadherin, through inhibition of the expression of SLUG, TWIST and SNAIL, three transcription factors involved in the epithelial mesenchymal transition (EMT) program. Finally, in a xenograft animal model, we showed that SFRP1 suppresses tumorigenicity of cancer cells in vivo. Conclusions: Taken together, these data strongly suggest that epigenetic silencing of SFRP genes leads to oncogenic activation of the Wnt pathway and contributes to cervical cancer progression through the EMT program.

Original languageEnglish
Pages (from-to)646-653
Number of pages8
JournalGynecologic Oncology
Volume112
Issue number3
DOIs
Publication statusPublished - Mar 2009
Externally publishedYes

Fingerprint

Wnt Signaling Pathway
Uterine Cervical Neoplasms
Signal Transduction
Catenins
Epithelial-Mesenchymal Transition
Neoplasms
Cadherins
Heterografts
Epigenomics
Small Interfering RNA
Carcinogenesis
Cytoplasm
Transcription Factors
Down-Regulation
Animal Models
Cell Line
Growth
Genes

Keywords

  • Cervical cancer
  • Epigenetic inactivation
  • SFRP genes
  • Wnt/β-catenin

ASJC Scopus subject areas

  • Obstetrics and Gynaecology
  • Oncology

Cite this

SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway. / Chung, Ming Tzeung; Lai, Hung Cheng; Sytwu, Huey Kang; Yan, Ming D.; Shih, Yu Lueng; Chang, Cheng Chang; Yu, Mu Hsien; Liu, Hang Seng; Chu, Da W.; Lin, Ya W.

In: Gynecologic Oncology, Vol. 112, No. 3, 03.2009, p. 646-653.

Research output: Contribution to journalArticle

Chung, MT, Lai, HC, Sytwu, HK, Yan, MD, Shih, YL, Chang, CC, Yu, MH, Liu, HS, Chu, DW & Lin, YW 2009, 'SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway', Gynecologic Oncology, vol. 112, no. 3, pp. 646-653. https://doi.org/10.1016/j.ygyno.2008.10.026
Chung, Ming Tzeung ; Lai, Hung Cheng ; Sytwu, Huey Kang ; Yan, Ming D. ; Shih, Yu Lueng ; Chang, Cheng Chang ; Yu, Mu Hsien ; Liu, Hang Seng ; Chu, Da W. ; Lin, Ya W. / SFRP1 and SFRP2 suppress the transformation and invasion abilities of cervical cancer cells through Wnt signal pathway. In: Gynecologic Oncology. 2009 ; Vol. 112, No. 3. pp. 646-653.
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AU - Lai, Hung Cheng

AU - Sytwu, Huey Kang

AU - Yan, Ming D.

AU - Shih, Yu Lueng

AU - Chang, Cheng Chang

AU - Yu, Mu Hsien

AU - Liu, Hang Seng

AU - Chu, Da W.

AU - Lin, Ya W.

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AB - Objectives: Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cancers, including cervical cancer. The secreted frizzled-related proteins (SFRPs) function as Wnt antagonists and play important implications in carcinogenesis. Recently, we have shown that SFRP1 and SFRP2 are frequently downregulated through promoter hypermethylation. However, the function of SFRP1 and SFRP2 in cervical cancer remains unclear. Methods: To improve our understanding of the role of SFRP1 and SFRP2 in cervical cancer cells, we use overexpression or shRNA approach in cervical cancer cell lines. Results: Restoration of the expression of SFRP1 and SFRP2 attenuated Wnt signaling in CaSki cells, decreased abnormal accumulation of free β-catenin in the nucleus, and suppressed cancer cell growth. In addition, different statuses of β-catenin accumulation in the cytoplasm of CaSki or HeLa3rd cells were observed, suggesting that different Wnt pathways are executed. Furthermore, we demonstrated that SFRP1 and SFRP2 enhance the expression of the epithelial marker E-cadherin, through inhibition of the expression of SLUG, TWIST and SNAIL, three transcription factors involved in the epithelial mesenchymal transition (EMT) program. Finally, in a xenograft animal model, we showed that SFRP1 suppresses tumorigenicity of cancer cells in vivo. Conclusions: Taken together, these data strongly suggest that epigenetic silencing of SFRP genes leads to oncogenic activation of the Wnt pathway and contributes to cervical cancer progression through the EMT program.

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