Epigenetic silencing of SFRP5 is related to malignant phenotype and chemoresistance of ovarian cancer through Wnt signaling pathway.
Oncogenic activation of the Wnt signaling pathway is common in cancers, but mutation of beta-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 platinum-based 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.
Su
Her-Young
HY
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Lai
Hung-Cheng
HC
Lin
Ya-Wen
YW
Liu
Chin-Yun
CY
Chen
Chi-Kuan
CK
Chou
Yu-Ching
YC
Lin
Shin-Ping
SP
Lin
Wen-Chi
WC
Lee
Hsin-Yi
HY
Yu
Mu-Hsien
MH
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D015153:Blotting, Western; D002945:Cisplatin / Q000494:pharmacology; D019175:DNA Methylation; D017931:DNA Primers; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002945:Cisplatin; D017931:DNA Primers; D005136:Eye Proteins; D008565:Membrane Proteins; D051153:Wnt Proteins; C118511:SFRP5 protein, human; D000094742:Secreted Frizzled-Related Proteins