Epigenetic silencing of SFRP5 is related to malignant phenotype and chemoresistance of ovarian cancer through Wnt signaling pathway

Her Young Su, Hung Cheng Lai, Ya Wen Lin, Chin Yun Liu, Chi Kuan Chen, Yu Ching Chou, Shin Ping Lin, Wen Chi Lin, Hsin Yi Lee, Mu Hsien Yu

Research output: Contribution to journalArticle

118 Citations (Scopus)

Abstract

Oncogenic activation of the Wnt signaling pathway is common in cancers, but mutation of b-catenin in ovarian cancer is rare. In addition to genetic events, epigenetic modification of secreted frizzled-related protein (SFRP) family has been shown to be important in regulating Wnt signaling. Although high degree of homology is observed in the same family, different SFRPs may have opposing effects on the same process. We reported recently that a Wnt antagonist, SFRP5, is downregulated frequently through promoter hypermethylation and that this hypermethylation is associated with overall survival in ovarian cancer. The aim of this study was to analyze the function of SFRP5 in ovarian cancer. Functional assays including measuring cell proliferation, invasion, colony formation and xenograft were performed using ovarian cancer cell lines with overexpression of SFRP5 or a short hairpin RNA silencing. The methylation status of SFRP5 in relation to cisplatin resistance in ovarian cancer patients was analyzed. Restoration of the expression of SFRP5 attenuated Wnt signaling in ovarian cancer cells and suppressed cancer cell growth, invasion of cells and tumorigenicity in mice. These effects were independent of the canonical pathway. The expression of SFRP5 inhibited epithelial-mesenchymal transition (EMT). The restoration of SFRP5 downregulated AKT2 and sensitized ovarian cancer cells to chemotherapy. These effects are consistent with the poor response to platinumbased chemotherapy in patients with methylation of SFRP5. Our data suggested that epigenetic silencing of SFRP5 leads to oncogenic activation of the Wnt pathway and contributes to ovarian cancer progression and chemoresistance through the TWIST-mediated EMT and AKT2 signaling.

Original languageEnglish
Pages (from-to)555-567
Number of pages13
JournalInternational Journal of Cancer
Volume127
Issue number3
DOIs
Publication statusPublished - Aug 1 2010
Externally publishedYes

Fingerprint

Wnt Signaling Pathway
Epigenomics
Ovarian Neoplasms
Phenotype
Epithelial-Mesenchymal Transition
Methylation
Down-Regulation
Drug Therapy
Catenins
RNA Interference
Heterografts
Small Interfering RNA
Cisplatin
Neoplasms
Cell Proliferation
Cell Line
Mutation
Survival
Growth

Keywords

  • Chemoresistance
  • Epigenetic inactivation
  • Ovarian cancer
  • SFRP5
  • Wnt signaling

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Epigenetic silencing of SFRP5 is related to malignant phenotype and chemoresistance of ovarian cancer through Wnt signaling pathway. / Su, Her Young; Lai, Hung Cheng; Lin, Ya Wen; Liu, Chin Yun; Chen, Chi Kuan; Chou, Yu Ching; Lin, Shin Ping; Lin, Wen Chi; Lee, Hsin Yi; Yu, Mu Hsien.

In: International Journal of Cancer, Vol. 127, No. 3, 01.08.2010, p. 555-567.

Research output: Contribution to journalArticle

Su, Her Young ; Lai, Hung Cheng ; Lin, Ya Wen ; Liu, Chin Yun ; Chen, Chi Kuan ; Chou, Yu Ching ; Lin, Shin Ping ; Lin, Wen Chi ; Lee, Hsin Yi ; Yu, Mu Hsien. / Epigenetic silencing of SFRP5 is related to malignant phenotype and chemoresistance of ovarian cancer through Wnt signaling pathway. In: International Journal of Cancer. 2010 ; Vol. 127, No. 3. pp. 555-567.
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