Gene Summary

Gene:SFRP4; secreted frizzled related protein 4
Aliases: PYL, FRP-4, FRPHE, FRZB-2, sFRP-4
Summary:Secreted frizzled-related protein 4 (SFRP4) is a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. SFRPs act as soluble modulators of Wnt signaling. The expression of SFRP4 in ventricular myocardium correlates with apoptosis related gene expression. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:secreted frizzled-related protein 4
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SFRP4 (cancer-related)

Wirbel J, Pyl PT, Kartal E, et al.
Meta-analysis of fecal metagenomes reveals global microbial signatures that are specific for colorectal cancer.
Nat Med. 2019; 25(4):679-689 [PubMed] Related Publications
Association studies have linked microbiome alterations with many human diseases. However, they have not always reported consistent results, thereby necessitating cross-study comparisons. Here, a meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of colorectal cancer (CRC, n = 768), which was controlled for several confounders, identified a core set of 29 species significantly enriched in CRC metagenomes (false discovery rate (FDR) < 1 × 10

van Andel H, Kocemba KA, Spaargaren M, Pals ST
Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options.
Leukemia. 2019; 33(5):1063-1075 [PubMed] Related Publications
Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors.

Marimuthu M, Andiappan M, Wahab A, et al.
Canonical Wnt pathway gene expression and their clinical correlation in oral squamous cell carcinoma.
Indian J Dent Res. 2018 May-Jun; 29(3):291-297 [PubMed] Related Publications
Aim: The aim of this study is to explore the prognostic significance and clinicopathological correlations of the Wnt pathway genes in a cohort of surgically treated patients with oral squamous cell carcinoma (OSCC) patients.
Settings and Design: A prospective genetic study on patients with OSCC was carried out during the period from July 2014 to January 2016. Informed consent from patients and institutional ethical approval for the study was obtained and the guidelines were strictly followed for collection of samples.
Subjects and Methods: Clinical data and mRNA expression analysis of ten genes in the canonical Wnt pathway were evaluated and their relationships with clinical and demographic variables were studied in 58 tissue samples. Wnt-3a, β-catenin, secreted frizzled-related proteins sFRP-1, sFRP-2, sFRP-4, sFRP-5, Wnt inhibitory factor 1, dickkopf-1, c-MYC, and cyclin-D1 from cancer (n = 29) and normal (n = 29) tissue samples were investigated using quantitative reverse transcription-polymerase chain reaction.
Statistical Analysis: Descriptive statistics were used to summarize the sample characteristics and clinical variables. If the data were normal, then parametric tests were used; otherwise, nonparametric alternatives were used. All the analyses were carried out using SPSS version 23.0 (IBM SPSS Inc., USA).
Results: Expression of sFRP-1, sFRP-2, and sFRP-5 in control samples and expression of c-MYC and cyclin D1 in cancer samples showed statistical significance. Significant expression of Wnt3A was observed among patients who had recurrence and were deceased.
Conclusion: Wnt3A, β-catenin, and cyclin D1 are recognized as key components of Wnt/β-catenin signaling. However, in this study, there was no significant expression of all the three genes in OSCC. The proto-oncogene c-MYC showed statistically significant upregulation in cancer tissue samples suggesting that the OSCC among South Indian population is primarily not mediated by the canonical Wnt signaling pathway.

Bahl C, Singh N, Behera D, Sharma S
High-order gene interactions between the genetic polymorphisms in Wnt and AhR pathway in modulating lung cancer susceptibility.
Per Med. 2017; 14(6):487-502 [PubMed] Related Publications
AIM: Genetic variations present within Wnt and AhR pathway might be related to the lung cancer susceptibility.
METHODS: A total of 555 subjects were genotyped using PCR-RFLP technique for polymorphic sites in DKK4, DKK3, DKK2, sFRP3, sFRP4, Axin2 and AhR. Multifactor dimensionality reduction method and classification and regression tree analysis was used.
RESULTS: Overall sFRP4
CONCLUSION: Both DKK2 and sFRP4 polymorphisms are found to play a crucial role; especially for smokers towards modulating risk for lung cancer. AhR variants are contributing maximally toward lung cancer risk.

Kitazawa S, Haraguchi R, Kitazawa R
Morphology-oriented epigenetic research.
Histochem Cell Biol. 2018; 150(1):3-12 [PubMed] Related Publications
Cytosine methylation plays a major role in the regulation of sequential and tissue-specific expression of genes. De novo aberrant DNA methylation and demethylation are also crucial processes in tumorigenesis and tumor progression. The mechanisms of how and when such aberrant methylation and demethylation occur in tumor cells are still obscure, however. To evaluate subtle epigenetic alteration among minor subclonal populations, morphology-oriented epigenetic analysis is requisite, especially where heterogeneity and flexibility are as notable as in the process of cancer progression and cellular differentiation at critical stages. Therefore, establishment of reliable morphology-oriented epigenetic studies has become increasingly important in not only the experimental but also the diagnostic field. By selecting a subset of cells based on characteristic morphological features disclosed by microdissection or in situ hybridization, we discovered how methylation at certain CpG sites outside of CpG islands would play a crucial epigenetic role in the versatility and flexibility of gene expression during cancer progression. In this review, we first introduce technical aspects of two morphology-oriented epigenetic studies: (1) histoendonuclease-linked detection of methylated sites of DNA (HELMET), and (2) padlock probe and rolling circle amplification (RCA) for in situ identification of methylated cytosine in a sequence-dependent manner. We then present our observation of a novel MeCP2-mediated gene-silencing mechanism through the addition of methylation to a single-CpG-locus upstream of the TATA-box of the receptor activator of NF-κB ligand (RANKL) and of secreted frizzled-related protein 4 (SFRP4) gene promoters.

Liu L, Chen F, Xiu A, et al.
Identification of Key Candidate Genes and Pathways in Endometrial Cancer by Integrated Bioinformatical Analysis
Asian Pac J Cancer Prev. 2018; 19(4):969-975 [PubMed] Free Access to Full Article Related Publications
Endometrial Cancer is the most common female genital tract malignancy, its pathogenesis is complex, not yet fully described. To identify key genes of Endometrial Cancer we downloaded the gene chip GSE17025 from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified through the GEO2R analysis tool. Functional and pathway enrichment analysis were performed for DEGs using DAVID database. The network of protein–protein-interaction (PPI) was established by STRING website and visualized by Cytoscape. Then, functional and pathway enrichment analysis of DEGS were performed by DAVID database. A total of 1000 significant differences genes were obtained, contain 362 up-regulated genes and 638 down-regulated genes. PCDH10, SLC6A2, OGN, SFRP4, TRH, ANGPTL, FOSB are down-regulated genes. The gene of IGH, CCL20, ELF5, LTF, ASPM expression level in tumor patients are up-regulated. Biological function of enrichment include metabolism of xenobiotics by cytochrome P450, MAPK signaling pathway, Serotonergic synapse, Protein digestion and absorption, IL-17 signaling pathway, Chemokine signaling pathway, HIF-1 signaling pathway, p53 signaling pathway. All in all, the current study to determine endometrial differentially expressed genes and biological function, comprehensive analysis of intrauterine membrane carcinoma pathogenesis mechanism, and might be used as molecular targets and diagnostic biomarkers for the treatment of endometrial cancer.

Cheong JH, Yang HK, Kim H, et al.
Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis.
Lancet Oncol. 2018; 19(5):629-638 [PubMed] Related Publications
BACKGROUND: Adjuvant chemotherapy after surgery improves survival of patients with stage II-III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II-III gastric cancer.
METHODS: In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II-III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival.
FINDINGS: We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2-92·0), 74·8% (69·9-80·1), and 66·0% (60·1-72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% [95% CI 73·5-87·1] vs 64·5% [56·8-73·3]; univariate hazard ratio 0·47 [95% CI 0·30-0·75], p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% [66·5-79·9] in patients who received chemotherapy plus surgery vs 72·5% [65·8-79·9] in patients who only had surgery; 0·93 [0·62-1·38], p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (p
INTERPRETATION: The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II-III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted.
FUNDING: Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare.

Song W, Qian L, Jing G, et al.
Aberrant expression of the sFRP and WIF1 genes in invasive non-functioning pituitary adenomas.
Mol Cell Endocrinol. 2018; 474:168-175 [PubMed] Related Publications
Non-functioning pituitary adenomas (NFPAs) are the most common pituitary tumors and mainly invade the sphenoid, cavernous sinus or dura mate. Aberrant regulation of the Wnt signaling pathway plays an important role in tumorigenesis. This study was designed to investigate the relationships between secreted frizzled-related proteins (sFRPs), WIF1 genes and the invasion of NFPAs by tissue microassays (TMAs) of samples from 163 patients. Significantly weaker staining of WIF1 and sFRP4 were detected in the invasive group compared with the non-invasive group by TMAs (p = 0.002, p < 0.001). Univariate analysis showed a significant correlation between tumor invasion and low expression of WIF1 and sFRP4 (p = 0.002, p < 0.001). A similar trend was observed when analyzing the mRNA and protein levels through RT-PCR and western blot experiments. Methylation of the WIF1 promoter was significantly increased in invasive NFPAs compared with the noninvasive group (p = 0.004). The average progression free survival time in the high WIF1 group was longer than that in the low WIF1 group (p = 0.025). Furthermore, RT-PCR measured the levels of 11 miRNAs targeting WIF1 according to the Targetscan database and PubMed. The levels of miRNA-137, miRNA-374a-5p and miRNA-374b-5p in the invasive group were 0.037-fold, 0.577-fold and 0.44-fold that of the noninvasive group (p = 0.003, p = 0.049 and p = 0.047). Overexpression of miRNA-137 could inhibit the proliferation and invasion of GH3 cells through cell viability and Transwell experiments (p < 0.05). Furthermore, the WIF1 level was upregulated after overexpression of miRNA-137 compared with miRNA-137-NC (control miRNA) in GH3 cells. Our data suggest that WIF1 may be potential biomarker for the aggressiveness of NFPAs. miRNA-137 plays an important role in the Wnt signaling pathway by affecting promoter methylation of WIF1.

Visweswaran M, Arfuso F, Dilley RJ, et al.
The inhibitory influence of adipose tissue-derived mesenchymal stem cell environment and Wnt antagonism on breast tumour cell lines.
Int J Biochem Cell Biol. 2018; 95:63-72 [PubMed] Related Publications
Tumours exhibit a heterogeneous mix of cell types that reciprocally regulate their growth in the tumour stroma, considerably affecting the progression of the disease. Both adipose-derived mesenchymal stem cells and Wnt signalling pathway are vital in driving breast tumour growth. Hence, we examined the effect of secreted factors released by adipose-derived mesenchymal stem cells, and further explored the anti-tumour property of the Wnt antagonist secreted frizzled-related protein 4 (sFRP4) on MCF-7 and MDA-MB-231 breast tumour cells. We observed that conditioned medium and extracellular matrix derived from adipose-derived mesenchymal stem cells inhibited tumour viability. The inhibitory effect of the conditioned medium was retained within its low molecular weight and non-protein component. The conditioned medium also induced apoptosis accompanied by a decrease in the mitochondrial membrane potential in tumour cells, Furthermore, it downregulated the protein expression of active β-catenin and Cyclin D1, which are major target proteins of the Wnt signalling pathway, and reduced the expression of anti-apoptotic protein Bcl-xL. The combination of conditioned medium and sFRP4 further potentiated the effects, depending on the tumour cell line and experimental assay. We conclude that factors derived from conditioned medium of adipose-derived mesenchymal stem cells and sFRP4 significantly decreased the tumour cell viability and migration rates (MCF-7), accompanied with an enhanced apoptotic activity through inhibition of canonical Wnt signalling. Besides giving an insight to possible paracrine interactions and influence of signalling pathways, reflective of a breast tumour microenvironment, this study emphasises the utilization of cell free-secreted factors and Wnt antagonists to improve conventional anti-cancer strategies.

Pereira TDSF, Diniz MG, França JA, et al.
The Wnt/β-catenin pathway is deregulated in cemento-ossifying fibromas.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; 125(2):172-178 [PubMed] Related Publications
OBJECTIVE: The molecular pathogenesis of cemento ossifying fibroma (COF) is unclear. The purpose of this study was to investigate mutations in 50 oncogenes and tumor suppressor genes, including APC and CTNNB1, in which mutations in COF have been previously reported. In addition, we assessed the transcriptional levels of the Wnt/β-catenin pathway genes in COF.
STUDY DESIGN: We used a quantitative polymerase chain reaction array to evaluate the transcriptional levels of 44 Wnt/β-catenin pathway genes in 6 COF samples, in comparison with 6 samples of healthy jaws. By using next-generation sequencing (NGS) in 7 COF samples, we investigated approximately 2800 mutations in 50 genes.
RESULTS: The expression assay revealed 12 differentially expressed Wnt/β-catenin pathway genes in COF, including the upregulation of CTNNB1, TCF7, NKD1, and WNT5 A, and downregulation of CTNNBIP1, FRZB, FZD6, RHOU, SFRP4, WNT10 A, WNT3 A, and WNT4, suggesting activation of the Wnt/β-catenin signaling pathway. NGS revealed 5 single nucleotide variants: TP53 (rs1042522), PIK3 CA (rs2230461), MET (rs33917957), KIT (rs3822214), and APC (rs33974176), but none of them was pathogenic.
CONCLUSIONS: Although NGS detected no oncogenic mutation, deregulation of key Wnt/β-catenin signaling pathway genes appears to be relevant to the molecular pathogenesis of COF.

Perumal V, Arfuso F, Chen Y, et al.
Delivery of expression constructs of secreted frizzled-related protein 4 and its domains by chitosan-dextran sulfate nanoparticles enhances their expression and anti-cancer effects.
Mol Cell Biochem. 2018; 443(1-2):205-213 [PubMed] Related Publications
In malignant mesothelioma (MM) cells, secreted frizzled-related protein 4 (SFRP4) expression is downregulated by promoter methylation. In this study, we evaluated the effect of encapsulated chitosan-dextran (CS-DS) nanoparticle formulations of SFRP4 and its cysteine-rich domain (CRD) and netrin-like domain (NLD) as means of SFRP4-GFP protein delivery and their effects in JU77 and ONE58 MM cell lines. CS-DS formulations of SFRP4, CRD, and NLD nanoparticles were prepared by a complex coacervation technique, and particle size ranged from 300 nm for empty particles to 337 nm for particles containing the proteins. Measurement of the zeta potential showed that all preparations were around 25 mV or above, suggesting stable formulation and good affinity for the DNA molecules. The CS-DS nanoparticle formulation maintained high integrity and entrapment efficiency. Gene delivery of SFRP4 and its domains showed enhanced biological effects in both JU77 and ONE58 cell lines when compared to the non-liposomal FUGENE

Sandsmark E, Andersen MK, Bofin AM, et al.
SFRP4 gene expression is increased in aggressive prostate cancer.
Sci Rep. 2017; 7(1):14276 [PubMed] Free Access to Full Article Related Publications
Increased knowledge of the molecular differences between indolent and aggressive prostate cancer is needed for improved risk stratification and treatment selection. Secreted frizzled-related protein 4 (SFRP4) is a modulator of the cancer-associated Wnt pathway, and previously suggested as a potential marker for prostate cancer aggressiveness. In this study, we investigated and validated the association between SFRP4 gene expression and aggressiveness in nine independent cohorts (n = 2157). By differential expression and combined meta-analysis of all cohorts, we detected significantly higher SFRP4 expression in cancer compared with normal samples, and in high (3-5) compared with low (1-2) Grade Group samples. SFRP4 expression was a significant predictor of biochemical recurrence in six of seven cohorts and in the overall analysis, and was a significant predictor of metastatic event in one cohort. In our study cohort, where metabolic information was available, SFRP4 expression correlated significantly with the concentrations of citrate and spermine, two previously suggested biomarkers for aggressive prostate cancer. SFRP4 immunohistochemistry in an independent cohort (n = 33) was not associated with aggressiveness. To conclude, high SFRP4 gene expression is associated with high Grade Group and recurrent prostate cancer after surgery. Future studies investigating the mechanistic and clinical usefulness of SFRP4 in prostate cancer are warranted.

Ng M, Thakkar D, Southam L, et al.
A Genome-wide Association Study of Dupuytren Disease Reveals 17 Additional Variants Implicated in Fibrosis.
Am J Hum Genet. 2017; 101(3):417-427 [PubMed] Free Access to Full Article Related Publications
Individuals with Dupuytren disease (DD) are commonly seen by physicians and surgeons across multiple specialties. It is an increasingly common and disabling fibroproliferative disorder of the palmar fascia, which leads to flexion contractures of the digits, and is associated with other tissue-specific fibroses. DD affects between 5% and 25% of people of European descent and is the most common inherited disease of connective tissue. We undertook the largest GWAS to date in individuals with a surgically validated diagnosis of DD from the UK, with replication in British, Dutch, and German individuals. We validated association at all nine previously described signals and discovered 17 additional variants with p ≤ 5 × 10

Delaney MA, Wan YW, Kim GE, et al.
A Role for Progesterone-Regulated sFRP4 Expression in Uterine Leiomyomas.
J Clin Endocrinol Metab. 2017; 102(9):3316-3326 [PubMed] Free Access to Full Article Related Publications
Context: Despite progesterone's key role in uterine smooth muscle tumorigenesis, the mechanisms by which it promotes the growth of uterine leiomyomas remain poorly understood.
Objective: The aim of this study was to identify gene products mediating the effects of progesterone in uterine leiomyomas.
Design: Gene expression profiling was used to identify putative progesterone-regulated genes differentially expressed in uterine leiomyomas, which were then studied in vitro.
Methods: Gene expression was comprehensively profiled with the Illumina WG BeadChip (version 2.6) and analyzed with a bioinformatic algorithm that integrates known protein-protein interactions. Genomic binding sites for progesterone receptor (PR) were interrogated by chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). Small interfering RNA was used to study gene function in primary cell lines.
Results: Our analyses identified secreted Frizzled-related protein 4 (sFRP4) as a key gene product functionally linked to PR activation whose expression was 2.6 times higher in leiomyomas than myometrium (n = 26, P < 0.01) and 2.5 times higher during the proliferative phase of the menstrual cycle (n = 26, P < 0.01). Direct binding between PR and sFRP4 promoter was observed by ChIP-qPCR. Robust overexpression of sFRP4 was also observed in primary cultures derived from leiomyoma. Progesterone preferentially inhibited sFRP4 expression and secretion in leiomyoma cultures in a dose-dependent manner sensitized by estradiol. Knockdown of sFRP4 inhibited proliferation and apoptosis in primary cultures of both myometrium and leiomyoma.
Conclusions: Overexpression of sFRP4 is a robust, progesterone-regulated feature of leiomyomas that increases smooth muscle proliferation. More work is needed to elucidate how progesterone's ability to modulate sFRP4 expression contributes to uterine smooth muscle tumorigenesis.

Deshmukh A, Kumar S, Arfuso F, et al.
Secreted Frizzled-related protein 4 (sFRP4) chemo-sensitizes cancer stem cells derived from human breast, prostate, and ovary tumor cell lines.
Sci Rep. 2017; 7(1):2256 [PubMed] Free Access to Full Article Related Publications
This study investigated molecular signals essential to sustain cancer stem cells (CSCs) and assessed their activity in the presence of secreted frizzled-related protein 4 (sFRP4) alone or in combination with chemotherapeutic drugs. SFRP4 is a known Wnt antagonist, and is also pro-apoptotic and anti-angiogenic. Additionally, sFRP4 has been demonstrated to confer chemo-sensitization and improve chemotherapeutic efficacy. CSCs were isolated from breast, prostate, and ovary tumor cell lines, and characterized using tumor-specific markers such as CD44

Vincent KM, Postovit LM
A pan-cancer analysis of secreted Frizzled-related proteins: re-examining their proposed tumour suppressive function.
Sci Rep. 2017; 7:42719 [PubMed] Free Access to Full Article Related Publications
Secreted frizzled-related proteins (SFRPs), containing five family members (SFRPs 1-5) are putative extracellular Wnt inhibitors. Given their abilities to inhibit Wnt signalling, as well as the loss of SFRP1 in many cancers, this family is generally considered to be tumour suppressive. In this study we analyzed gene expression, promoter methylation and survival data from over 8000 tumour and normal samples from 29 cancers in order to map the context-specific associations of SFRPs 1-5 with patient survival, gene silencing and gene expression signatures. We show that only SFRP1 associates consistently with tumour suppressive functions, and that SFRP2 and SFRP4 typically associate with a poor prognosis concomitant with the expression of genes associated with epithelial-to-mesenchymal transition. Moreover, our results indicate that while SFRP1 is lost in cancer cells via the process of DNA methylation, SFRP2 and 4 are likely derived from the tumour stroma, and thus tend to increase in tumours as compared to normal tissues. This in-depth analysis highlights the need to study each SFRP as a separate entity and suggests that SFRP2 and SFRP4 should be approached as complex matricellular proteins with functions that extend far beyond their putative Wnt antagonistic ability.

Wang H, Duan XL, Qi XL, et al.
Concurrent Hypermethylation of
Mol Cells. 2017; 40(1):45-53 [PubMed] Free Access to Full Article Related Publications
Aberrant hypermethylation of Wnt antagonists has been observed in gastric cancer. A number of studies have focused on the hypermethylation of a single Wnt antagonist and its role in regulating the activation of signaling. However, how the Wnt antagonists interacted to regulate the signaling pathway has not been reported. In the present study, we systematically investigated the methylation of some Wnt antagonist genes (

Murakami T, Mitomi H, Yao T, et al.
Epigenetic regulation of Wnt/β-catenin signal-associated genes in gastric neoplasia of the fundic gland (chief cell-predominant) type.
Pathol Int. 2017; 67(3):147-155 [PubMed] Related Publications
Gastric neoplasia of the fundic gland (chief cell-predominant) type (GNCCP) is a rare variant of gastric tumor. This tumor is associated with activation of the Wnt/β-catenin signaling pathway; however, the mechanisms underlying this activation remain unknown. To elucidate potential roles of Wnt/β-catenin signal-associated gene methylation in GNCCP, we performed β-catenin immunostaining and methylation-specific polymerase chain reaction (PCR) for their associated genes, including SFRPs, APC, AXIN2, and MCC, in 26 GNCCPs [i.e., 11 intramucosal (GNCCP-Ms) and 15 submucosal tumors (GNCCP-SMs)], and compared with 27 fundic gland polyps (FGPs), 12 FGPs with dysplasia (FGP-Ds), 27 conventional gastric adenocarcinomas (CGAs). Nuclear β-catenin labeling indices were higher in GNCCPs and CGAs than in FGPs and FGP-Ds. SFRPs, APC, and AXIN2 were more frequently methylated in GNCCPs and CGAs (SFRP1, 88%/96%; SFRP2, 85%/93%; SFRP4, 73%/81%; APC, 81%/81%; AXIN2, 81%/85%; respectively) than in FGPs and FGP-Ds (37%/50%; 41%/42%; 41%/58%; 37%/33%; 41%/50%; respectively). A significant correlation was seen between nuclear β-catenin expression and methylation of SFRP1 in GNCCPs. Furthermore, nuclear β-catenin expression was significantly frequent in high-methylated GNCCPs than in low-methylated tumors. In conclusion, our results suggest that activation of this pathway, mediated by gene methylation, may be associated with progression of some GNCCP cases, similar to CGAs.

Huang YW, Gu F, Dombkowski A, et al.
Black raspberries demethylate Sfrp4, a WNT pathway antagonist, in rat esophageal squamous cell papilloma.
Mol Carcinog. 2016; 55(11):1867-1875 [PubMed] Related Publications
Aberrant methylation of DNA is a common event in the development of cancers, including squamous cell carcinoma (SCC) of the human esophagus. In the present study, we determined: (a) whether aberrant DNA methylation also occurs in the development of N-nitrosomethylbenzylamine (NMBA)-induced tumorigenesis in the rat esophagus, a model of human esophageal SCC; and (b) if so, whether dietary black raspberries (BRBs) are capable of preventing this aberrant DNA methylation. A diet containing 5% BRBs inhibited the development of NMBA-induced tumors in the rat esophagus. This inhibition was associated with reduced mRNA levels of the DNA methyltransferases, Dnmt1 and Dnmt3b, in both dysplastic lesions and in papillomas of the esophagus. In addition, promoter methylation of Sfrp4, a WNT pathway antagonist, was significantly reduced by the berry diet, and this was associated with decreased nuclear localization of β-CATENIN and reduced expression of c-MYC protein in NMBA-treated esophagi. Decreased promoter methylation of Sfrp4 correlated with decreased expression of Dmnt3b and, ultimately, with increased Sfrp4 mRNA expression. This suggests that epigenetic alterations in NMBA-induced rat esophageal tumorigenesis recapitulate epigenetic events in human esophageal SCC, and that BRBs could be useful in preventing the aberrant DNA methylation involved in the development of human esophageal SCC. © 2015 Wiley Periodicals, Inc.

Lee KW, Lee SS, Hwang JE, et al.
Development and Validation of a Six-Gene Recurrence Risk Score Assay for Gastric Cancer.
Clin Cancer Res. 2016; 22(24):6228-6235 [PubMed] Free Access to Full Article Related Publications
PURPOSE: This study was aimed at developing and validating a quantitative multigene assay for predicting tumor recurrence after gastric cancer surgery.
EXPERIMENTAL DESIGN: Gene expression data were generated from tumor tissues of patients who underwent surgery for gastric cancer (n = 267, training cohort). Genes whose expression was significantly associated with activation of YAP1 (a frequently activated oncogene in gastrointestinal cancer), 5-year recurrence-free survival, and 5-year overall survival were first identified as candidates for prognostic genes (156 genes, P < 0.001). We developed the recurrence risk score (RRS) by using quantitative RT-PCR to identify genes whose expression levels were significantly associated with YAP1 activation and patient survival in the training cohort.
RESULTS: We based the RRS assay on 6 genes, IGFBP4, SFRP4, SPOCK1, SULF1, THBS, and GADD45B, whose expression levels were significantly associated with YAP1 activation and prognosis in the training cohort. The RRS assay was further validated in an independent cohort of 317 patients. In multivariate analysis, the RRS was an independent predictor of recurrence [HR, 1.6; 95% confidence interval (CI), 1.02-2.4; P = 0.03]. In patients with stage II disease, the RRS had an HR of 2.9 (95% CI, 1.1-7.9; P = 0.03) and was the only significant independent predictor of recurrence.
CONCLUSIONS: The RRS assay was a valid predictor of recurrence in the two cohorts of patients with gastric cancer. Independent prospective studies to assess the clinical utility of this assay are warranted. Clin Cancer Res; 22(24); 6228-35. ©2016 AACR.

García-Tobilla P, Solórzano SR, Salido-Guadarrama I, et al.
SFRP1 repression in prostate cancer is triggered by two different epigenetic mechanisms.
Gene. 2016; 593(2):292-301 [PubMed] Related Publications
Worldwide, prostate cancer (PCa) is the second cause of death from malignant tumors among men. Establishment of aberrant epigenetic modifications, such as histone post-translational modifications (PTMs) and DNA methylation (DNAme) produce alterations of gene expression that are common in PCa. Genes of the SFRP family are tumor suppressor genes that are frequently silenced by DNA hypermethylation in many cancer types. The SFRP family is composed of 5 members (SFRP1-5) that modulate the WNT pathway, which is aberrantly activated in PCa. The expression of SFRP genes in PCa and their regulation by DNAme has been controversial. Our objective was to determine the gene expression pattern of the SFRP family in prostatic cell lines and fresh frozen tissues from normal prostates (NP), benign prostatic hyperplasia (BPH) and prostate cancer (PCa), by qRT-PCR, and their DNAme status by MSP and bisulfite sequencing. In prostatic cancer cell lines, the 5 SFRPs showed significantly decreased expression levels compared to a control normal prostatic cell line (p<0.0001). In agreement, SFRP1 and SFRP5 genes showed decreased expression levels in CaP fresh frozen tissues compared to NP (p<0.01), while a similar trend was observed for SFRP2. Conversely, increased levels of SFRP4 expression were found in PCa compared to BPH (p<0.01). Moreover, SFRP2, SFRP3, and SFRP5 showed DNA hypermethylation in PCa cell lines. Interestingly, we observed DNA hypermethylation at the promoter of SFRP1 in the PC3 cell line, but not in LNCaP. However, in the LNCaP cell line we found an aberrant gain of the repressive histone posttranslational modification Histone H3 lysine 27 trimethylation (H3K27me3). In conclusion, decreased expression by DNA hypermethylation of SFRP5 is a common feature of PCa, while decreased expression of SFRP1 can be due to DNA hypermethylation, but sometimes an aberrant gain of the histone mark H3K27me3 is observed instead.

Ghoshal A, Ghosh SS
Antagonizing canonical Wnt signaling pathway by recombinant human sFRP4 purified from E. coli and its implications in cancer therapy.
Mol Cell Biochem. 2016; 418(1-2):119-35 [PubMed] Related Publications
The Wnt signaling pathway plays a predominant role in aberrant proliferation in myriad of cancers. In non-cancerous cells, Wnts are blocked by the secreted frizzled-related proteins (sFRPs) that are generally downregulated in cancer cells. We have purified and characterized bacterially expressed glutathione S-transferase-tagged SFRP4 from a novel clone generated from human cell origin. Cervical cancer (HeLa) and lung cancer (A549) cells, in which Wnt and associated genes were found to be expressed, were treated with the purified recombinant sFRP4, which revealed a significant dose-dependent cell growth inhibition up to 40 %. The current investigation on functionality of this bacterially produced recombinant sFRP4 in arresting cancer cell proliferation is the first of its kind, where G2/M phase arrest and early apoptosis were evident. Increase in phosphorylated β-catenin in sFRP4 treatment indicated inhibition of Wnt pathway, which was further confirmed by downregulation of pro-proliferative genes, namely cyclin D1, c-myc, and survivin. Functional activity of recombinant sFRP4 was further exploited in co-therapy module with chemotherapeutic drugs to decipher molecular events. Collectively, our study on purified recombinant sFRP4 from bacterial host holds great promise in targeting Wnt signaling for exploring new strategies to combat cancer.

Wu Y, Liu C, Yu S, et al.
Assessment of sFRP4 as a bio-marker for predicting aggressiveness and recurrence of growth hormone-secreting pituitary adenomas.
Oncol Rep. 2016; 35(5):2991-9 [PubMed] Related Publications
The association of sFRP4 expression with aggressiveness and recurrence of growth hormone (GH)-secreting pituitary adenomas was investigated. Ten normal pituitary and 52 GH-secreting pituitary adenoma specimens were classified into three groups: normal pituitary (control) group, non-aggressive group, and aggressive group, according to preoperative evaluation by magnetic resonance imaging (MRI)/computed tomography (CT). Expression of sFRP4 was determined by quantitative real-time polymerase chain reaction (qRT-PCR), western blot analysis, and tissue microarrays, to assess the association between sFRP4 and aggressiveness. Follow-up information of all 52 patients was collected to evaluate the impact of sFRP4 expression on the recurrence/progression of GH-secreting pituitary adenomas. qRT-PCR results showed a lower level of sFRP4 mRNA in the aggressive group, as compared to that in the non-aggressive group (P=0.001). A similar trend was observed on western blot analysis for sFRP4 protein expression (P=0.004). On analysis by tissue microarrays, weak sFRP4 expression was detected in the aggressive group (10/15, 66.7%). Univariate analysis showed a significant relationship between low sFRP4 expression and aggressiveness (P=0.024). On multivariate analysis weak sFRP4 expression was found to be an independent factor of recurrence/progression (odds ratio: 0.063, P=0.026). Methylation of the sFRP4 promoter was increased in low sFRP4 staining group compared to that in the high sFRP4 staining group (P<0.001). In this study, weak sFRP4 expression appeared to predict aggressive behavior, and was associated with recurrence/progression of GH-secreting pituitary adenomas. Methylation of the sFRP4 promoter may account for the low sFRP4 expression.

Kishino T, Niwa T, Yamashita S, et al.
Integrated analysis of DNA methylation and mutations in esophageal squamous cell carcinoma.
Mol Carcinog. 2016; 55(12):2077-2088 [PubMed] Related Publications
The recent development of next-generation sequencing technology for extensive mutation analysis, and beadarray technology for genome-wide DNA methylation analysis has made it possible to obtain integrated pictures of genetic and epigenetic alterations, using the same cancer samples. In this study, we aimed to characterize such a picture in esophageal squamous cell carcinomas (ESCCs). Base substitutions of 55 cancer-related genes and copy number alterations (CNAs) of 28 cancer-related genes were analyzed by targeted sequencing. Forty-four of 57 ESCCs (77%) had 64 non-synonymous somatic mutations, and 24 ESCCs (42%) had 35 CNAs. A genome-wide DNA methylation analysis using an Infinium HumanMethylation450 BeadChip array showed that the CpG island methylator phenotype was unlikely to be present in ESCCs, a different situation from gastric and colon cancers. Regarding individual pathways affected in ESCCs, the WNT pathway was activated potentially by aberrant methylation of its negative regulators, such as SFRP1, SFRP2, SFRP4, SFRP5, SOX17, and WIF1 (33%). The p53 pathway was inactivated by TP53 mutations (70%), and potentially by aberrant methylation of its downstream genes. The cell cycle was deregulated by mutations of CDKN2A (9%), deletions of CDKN2A and RB1 (32%), and by aberrant methylation of CDKN2A and CHFR (9%). In conclusion, ESCCs had unique methylation profiles different from gastric and colon cancers. The genes involved in the WNT pathway were affected mainly by epigenetic alterations, and those involved in the p53 pathway and cell cycle regulation were affected mainly by genetic alterations. © 2016 Wiley Periodicals, Inc.

Zang B, Huang G, Wang X, Zheng S
HPV-16 E6 promotes cell growth of esophageal cancer via downregulation of miR-125b and activation of Wnt/β-catenin signaling pathway.
Int J Clin Exp Pathol. 2015; 8(10):13687-94 [PubMed] Free Access to Full Article Related Publications
High-risk human papillomavirus (HPV) is a possible cause of esophageal cancer. However, the molecular pathogenesis of HPV-infected esophageal cancer remains unclear. The expression levels of some microRNAs including miR-125b have been negatively correlated with HPV infection, and miR-125b downregulation is associated with tumorigenesis. In addition, Wnt/β-catenin signaling pathway has been suggested to play an important role in esophageal cancer (EC). We examined miR-125b and Wnt/β-catenin signaling pathway in HPV-16 E6 promoted tumor progression in EC. HPV-16 E6 transfection decreased markedly the expression levels of miR-125b and promoted the colony formation in the Eca 109 and Kyse 150 cell lines, and restoration of miR-125b expression level antagonized the increased colony formation in HPV-16 E6 transfected cell lines. We also demonstrated that overexpression of E6 upregulated the Wnt/β-catenin signaling activity via modulating the multiple regulators including TLE1, GSK3β, and sFRP4. Overexpression of miR-125b restored the expression levels of these proteins. Expression of miR-125b was lower in HPV-16 E6 positive esophageal cancer tissues, and was negatively correlated with E6 mRNA levels. Our results indicate that HPV-16 E6 promotes tumorigenesis in EC via down-regulation of miR-125b, and this underlying mechanism may be involved in the activation of the Wnt/β-catenin signaling pathway.

Yadav A, Gupta A, Yadav S, et al.
Association of Wnt signaling pathway genetic variants in gallbladder cancer susceptibility and survival.
Tumour Biol. 2016; 37(6):8083-95 [PubMed] Related Publications
Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with adverse prognosis and poor survival. Wnt signaling plays an important role in embryonic development and regeneration of tissues in all the species. Deregulation of expression and mutations in this pathway may lead to disease state such as cancer. In this study, we assessed the association of common germline variants of Wnt pathway genes (SFRP2, SFRP4, DKK2, DKK3, WISP3, APC, β-catenin, AXIN-2, GLI-1) to evaluate their contribution in predisposition to GBC and treatment outcomes. The study included 564 GBC patients and 250 controls. Out of 564, 200 patients were followed up for treatment response and survival. Tumor response (RECIST 1.1) was recorded in 116 patients undergoing non-adjuvant chemotherapy (NACT). Survival was assessed by Kaplan-Meier curve and Cox-proportional hazard regression. Single locus analysis showed significant association of SFRP4 rs1802073G > T [p value = 0.0001], DKK2 rs17037102C > T [p value = 0.0001], DKK3 rs3206824C > T [p value = 0.012], APC rs4595552 A/T [p value = 0.021], APC rs11954856G > T [p value = 0.047], AXIN-2 rs4791171C > T [p value = 0.001], β-catenin rs4135385A > G [p value = 0.031], and GLI-1 rs222826C > G [p value = 0.001] with increased risk of GBC. Gene-gene interaction using GMDR analysis predicted APC rs11954856 and AXIN2 rs4791171 as significant in conferring GBC susceptibility. Cox-proportional hazard model showed GLI-1 rs2228226 CG/GG and AXIN-2 rs4791171 TT genotype higher hazard ratio. In recursive partitioning, AXIN-2 rs4791171 TT genotype showed higher mortality and hazard. Most of studied genetic variants influence GBC susceptibility. APC rs11954856, GLI-1 rs2228226, and AXIN-2 rs4791171 were found to be associated with poor survival in advanced GBC patients.

Kierulf-Vieira KS, Sandberg CJ, Grieg Z, et al.
Wnt inhibition is dysregulated in gliomas and its re-establishment inhibits proliferation and tumor sphere formation.
Exp Cell Res. 2016; 340(1):53-61 [PubMed] Related Publications
Evidence indicates that the growth of glioblastoma (GBM), the most common and malignant primary brain cancer, is driven by glioma stem cells (GSCs) resistant to current treatment. As Wnt-signaling is pivotal in stem cell maintenance, we wanted to explore its role in GSCs with the objective of finding distinct signaling mechanisms that could serve as potential therapeutic targets. We compared gene expression in GSCs (n=9) and neural stem cells from the adult human brain (ahNSC; n=3) to identify dysregulated genes in the Wnt signaling pathway. This identified a six-gene Wnt signature present in all nine primary GSC cultures, and the combined expression of three of these genes (SFRP1, SFRP4 and FZD7) reduced median survival of glioma patients from 38 to 17 months. Treatment with recombinant SFRP1 protein in primary cell cultures downregulated nuclear β-catenin and decreased in vitro proliferation and sphere formation in a dose-dependent manner. Furthermore, expressional and functional analysis of SFRP1-treated GSCs revealed that SFRP1 halts cell cycling and induces apoptosis. These observations demonstrate that Wnt signaling is dysregulated in GSC, and that inhibition of the Wnt pathway could serve as a therapeutic strategy in the treatment of GBM.

Mortensen MM, Høyer S, Lynnerup AS, et al.
Expression profiling of prostate cancer tissue delineates genes associated with recurrence after prostatectomy.
Sci Rep. 2015; 5:16018 [PubMed] Free Access to Full Article Related Publications
Prostate cancer is a leading cause of cancer death amongst males. The main clinical dilemma in treating prostate cancer is the high number of indolent cases that confer a significant risk of overtreatment. In this study, we have performed gene expression profiling of tumor tissue specimens from 36 patients with prostate cancer to identify transcripts that delineate aggressive and indolent cancer. Key genes were validated using previously published data and by tissue microarray analysis. Two molecular subgroups were identified with a significant overrepresentation of tumors from patients with biochemical recurrence in one of the groups. We successfully validated key transcripts association with recurrence using two publically available datasets totaling 669 patients. Twelve genes were found to be independent predictors of recurrence in multivariate logistical regression analysis. SFRP4 gene expression was consistently up regulated in patients with recurrence in all three datasets. Using an independent cohort of 536 prostate cancer patients we showed SFRP4 expression to be an independent predictor of recurrence after prostatectomy (HR = 1.35; p = 0.009). We identified SFRP4 to be associated with disease recurrence. Prospective studies are needed in order to assess the clinical usefulness of the identified key markers in this study.

Yilmaz M, Donmez G, Kacan T, et al.
Significant Association Between Polymorphisms of Wnt Antagonist Genes and Lung Cancer.
J Investig Med. 2015; 63(8):935-41 [PubMed] Related Publications
Further elucidation of the molecular mechanisms underlying lung cancer (LC) is essential for the development of new effective therapeutic agents. Recently, involvement of Wnt antagonists in oncogenesis has been demonstrated in several cancers. The investigation of their contribution to lung carcinogenesis is still under investigation. We aimed to investigate whether there is a susceptibility or preventive effect of Wnt antagonist gene polymorphisms on the development and/or prognosis of LC. We investigated 110 LC patients and 160 controls. Single-nucleotide polymorphisms of Wnt antagonist genes including DKK2 (rs17037102), DKK3 (rs3206824), DKK3 intron4 G/C (rs7396187), DKK4 (rs2073664), and sFRP4 (rs1802074) were analyzed using nested polymerase chain reaction and restriction fragment length polymorphism. Results showed that patients with DKK3 AA compared with controls have a decreased risk of LC (adjusted for smoking habit, body mass index, and familial history) (P = 0.02; odds ratio [OR],0.08; 95% confidence interval [95% CI], 0.01-0.7). It was found that, for sFRP4 polymorphism, patients with GG and GA genotypes versus AA genotype controls showed a decreased risk for LC (P = 0.01; [OR, 0.19; 95% CI, 0.05-0.73 for GG genotype]; [OR = 0.18, 95% CI, 0.04-0.72 for GA genotype]). In addition, a decreased risk of LC was also found for the genotype combination of DKK3 (rs3206824) GG and sFRP4 AG + GG (P = 0.004; OR, 0.12; 95% CI, 0.02-0.58). We suggest that these 2 polymorphisms have a protective effect on LC in this study.

Liang J, Kang X, Halifu Y, et al.
Secreted frizzled-related protein promotors are hypermethylated in cutaneous squamous carcinoma compared with normal epidermis.
BMC Cancer. 2015; 15:641 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The Wnt signaling pathway is abnormally activated in many human cancers. Secreted frizzled-related proteins (SFRPs) function as negative regulators of Wnt signaling and play an important role in carcinogenesis. SFRP promoter hypermethylation has often been identified in human cancers; however, the precise role of SFRPs in cutaneous squamous cell carcinoma (SCC) is unclear.
METHODS: The methylation status of the SFRP family was analyzed in an age-and sex-matched case-control study, including 40 cutaneous SCC cases and 40 normal controls, using the MassARRAY EpiTYPER system.
RESULTS: The methylation rate of SFRP1, SFRP2, SFRP4, and SFRP5 promoters was significantly higher in cutaneous SCC tissues than in adjacent tissue and normal skin samples.
DISCUSSION: Our manuscript mainly discussed the average methylation rate of SFRPs (SFRP1, SFRP2, SFRP4, and SFRP5) promoters are significantly high in tumor tissue samples and the average CpG island methylation rate among different pathological levels of cutaneous SCC between these genes are different.
CONCLUSIONS: Our findings suggest that promoter hypermethylation of SFRPs is associated with the development of carcinoma, and could be a useful tumor marker for cutaneous SCC and other types of cancers.

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