Secreted frizzled-related protein 4 and its implications in cancer and apoptosis
Secreted frizzled-related protein 4 (SFRP4) is a glycoprotein that acts as an antagonist of Wnt ligands, causing inhibition of the canonical Wnt signalling pathway. First noticed due to high expression levels during times of increased apoptosis, SFRP4 has been implicated in cell proliferation and differentiation and plays an important role in carcinogenesis. Many tumours such as endometrial, cervical, ovarian, prostate, bladder, colorectal, mesothelioma, pancreatic, renal, and oesophageal tumours are characterised by aberrant promoter hypermethylation, which causes variations in the expression level of SFRP4 when compared to normal cells. Combined experimental data appear to confirm the suggested role of SFRP4 as a local initiator of apoptosis; however, increased SFRP4 expression may not always correlate with an increase in apoptosis, possibly due to the complex interactions between different signalling pathways. SFRP4 can be explored for its use in novel therapeutic modalities as well as being a potential diagnostic biomarker.
KeywordsSFRP4 Apoptosis Cancer Wnt signalling
AD was supported by a grant from Cancer Council. Raine Medical Foundation. and School of Biomedical Sciences Strategic Research Funds, Curtin University. VP was supported by Curtin University International Postgraduate Research Scholarship.
Conflicts of interest
- 1.Miller JR. The Wnts. Genome biology 2002;3:REVIEWS3001.Google Scholar
- 5.Surana R, Sikka S, Cai W, Shin EM, Warrier SR, Tan HJ, et al. Secreted frizzled related proteins: implications in cancers. Biochim Biophys Acta. 1845;2014:53–65.Google Scholar
- 28.van der Meide WF, Snellenberg S, Meijer CJ, Baalbergen A, Helmerhorst TJ, van der Sluis WB, et al. Promoter methylation analysis of WNT/beta-catenin signaling pathway regulators to detect adenocarcinoma or its precursor lesion of the cervix. Gynecol Oncol. 2011;123:116–22.CrossRefPubMedGoogle Scholar
- 35.Saran U, Arfuso F, Zeps N, Dharmarajan A. Secreted frizzled-related protein 4 expression is positively associated with responsiveness to cisplatin of ovarian cancer cell lines in vitro and with lower tumour grade in mucinous ovarian cancers. BMC Cell Biol. 2012;13:25.CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Horvath LG, Henshall SM, Kench JG, Saunders DN, Lee CS, Golovsky D, et al. Membranous expression of secreted frizzled-related protein 4 predicts for good prognosis in localized prostate cancer and inhibits PC3 cellular proliferation in vitro. Clin Cancer Res. 2004;10:615–25.CrossRefPubMedGoogle Scholar
- 54.Wu Y, Bai J, Li Z, Wang F, Cao L, Liu C, et al. Low expression of secreted frizzled-related protein 4 in aggressive pituitary adenoma. Pituitary 2014.Google Scholar
- 67.Granados-Principal S, Quiles JL, Ramirez-Tortosa C, Camacho-Corencia P, Sanchez-Rovira P, Vera-Ramirez L, et al. Hydroxytyrosol inhibits growth and cell proliferation and promotes high expression of sfrp4 in rat mammary tumours. Mol Nutr Food Res. 2011;55 Suppl 1:S117–26.CrossRefPubMedGoogle Scholar
- 84.Warrier S, Bhuvanalakshmi G, Arfuso F, Rajan G, Millward M, Dharmarajan A. Cancer stem-like cells from head and neck cancers are chemosensitized by the Wnt antagonist, sFRP4, by inducing apoptosis, decreasing stemness, drug resistance and epithelial to mesenchymal transition. Cancer Gene Ther. 2014;21:381–8.CrossRefPubMedGoogle Scholar