Gene Summary

Gene:SFRP2; secreted frizzled related protein 2
Aliases: FRP-2, SARP1, SDF-5
Summary:This gene encodes 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. Methylation of this gene is a potential marker for the presence of colorectal cancer. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:secreted frizzled-related protein 2
Source:NCBIAccessed: 01 September, 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 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 01 September, 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: SFRP2 (cancer-related)

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.

Wang JR, Liu B, Zhou L, Huang YX
MicroRNA-124-3p suppresses cell migration and invasion by targeting ITGA3 signaling in bladder cancer.
Cancer Biomark. 2019; 24(2):159-172 [PubMed] Related Publications
BACKGROUND: A growing body of studies have demonstrated the aberrant expression of microRNAs (miRNAs) contributes to human tumor metastasis. MicroRNA-124-3p (miR-124-3p), which is down-regulated in various cancers, has been found to be involved in several signaling pathways relevant to tumor cell migration and invasion. However, the roles of miR-124-3p in human bladder cancer remain unclear. This study aims to investigate the functional significance of miR-124-3p and to understand how it targets the integrin receptor, and thus affects the progression of human bladder cancer.
METHODS: Clinical specimens from 36 patients and three human bladder cancer cell lines were analyzed for miR-124-3p and integrin α3 (ITGA3) . To investigate the effects of miR-124-3p and ITGA3 on proliferation of bladder cancer cells, the MTT assay, colon-formation assay and flow cytometry were performed. In addition, wound healing assay and transwell assay were carried out to examine the migration and invasion of the bladder cancer cells transfected with miR-124-3p mimics or si-ITGA3. The luciferase reporter assay, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were applied to validate the miR-124-3p directly binding with ITGA3. Finally, western blot was used to examine the expression level of the proteins involved in FAK/PI3K/AKT and FAK/Src signal pathway as well as epithelial-mesenchymal transition (EMT) process.
RESULTS: The down-regulation of miR-124-3p and up-regulation of ITGA3 were observed in clinical specimens and bladder cancer cell lines. Overexpression of miR-124-3p or silencing ITGA3 inhibited tumor cell migration and invasion. Luciferase assay confirmed miR-124-3p directly targets ITGA3, and western blot suggested that miR-124-3p plays a crucial role in the EMT and metastasis of human bladder cancer through FAK/PI3K/AKT and FAK/Src signaling mechanism. Also, by targeting ITGA3, miR-124-3p can modulate the expression of N- and E-cadherin, and thus inhibit the EMT.
CONCLUSIONS: By targeting ITGA3 and downstream FAK/PI3K/AKT and FAK/Src signaling pathways, miR-124-3p suppresses cell migration and invasion in bladder cancer. Our study reasonably speculates that miR-124-3p can be potentially developed as a therapeutic target and prognostic biomarker for bladder cancer.

Reyes I, Reyes N, Suriano R, et al.
Gene expression profiling identifies potential molecular markers of papillary thyroid carcinoma.
Cancer Biomark. 2019; 24(1):71-83 [PubMed] Related Publications
BACKGROUND: Thyroid cancer is the most common endocrine malignancy worldwide, with the predominant form papillary thyroid carcinoma (PTC) representing approximately 80% of cases.
OBJECTIVE: This study was addressed to identify potential genes and pathways involved in the pathogenesis of PTC and potential novel biomarkers for this disease.
METHODS: Gene expression profiling was carried out by DNA microarray technology. Validation of microarray data by qRT-PCR, western blot, and enzyme linked immunosorbent assay was also performed in a selected set of genes and gene products, with the potential to be used as diagnostic or prognostic biomarkers, such as those associated with cell adhesion, extracellular matrix (ECM) remodeling and immune/inflammatory response.
RESULTS: In this study we found that upregulation of extracellular activities, such as proteoglycans, ECM-receptor interaction, and cell adhesion molecules, were the most prominent feature of PTC. Significantly over-expressed genes included SDC1 (syndecan 1), SDC4 (syndecan 4), KLK7 (kallikrein-related peptidase 7), KLK10 (kallikrein-related peptidase 10), SLPI (secretory leukocyte peptidase inhibitor), GDF15 (growth/differentiation factor-15), ALOX5 (arachidonate 5-lipoxygenase), SFRP2 (secreted Frizzled-related protein 2), among others. Further, elevated KLK10 levels were detected in patients with PTC. Many of these genes belong to KEGG pathway "Proteoglycans in cancer".
CONCLUSIONS: Using DNA microarray analysis allowed the identification of genes and pathways with known important roles in malignant transformation, and also the discovery of novel genes that may be potential biomarkers for PTC.

Mäki-Nevala S, Valo S, Ristimäki A, et al.
DNA methylation changes and somatic mutations as tumorigenic events in Lynch syndrome-associated adenomas retaining mismatch repair protein expression.
EBioMedicine. 2019; 39:280-291 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR.
METHODS: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n = 49) and MMR-proficient (MMR-P, n = 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing.
FINDINGS: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (IGF2, NEUROG1, CRABP1, and CDKN2A) and TSGs (SFRP1 and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas.
INTERPRETATION: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. FUND: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid Juselius Foundation, and HiLIFE.

Strzelczyk JK, Krakowczyk Ł, Owczarek AJ
Methylation status of SFRP1, SFRP2, RASSF1A, RARβ and DAPK1 genes in patients with oral squamous cell carcinoma.
Arch Oral Biol. 2019; 98:265-272 [PubMed] Related Publications
Our study assessed the methylation status of the SFRP1, SFRP2, RASSF1A, RARβ and DAPK1 genes, which are associated with epigenetic silencing in cancers. In a group of 75 patients with oral squamous cell carcinoma, aberrant methylation was detected using methylation-specific PCR in tumours and matched margins. Our results showed significantly higher methylation frequency in tumours than in surgical margin of SFRP2 (26.6% vs 11.9%, p < 0.05) and DAPK1 (65.3% vs 41.3%, p < 0.01) genes. Moreover, methylation of the SFRP1 and DAPK1 genes was associated with older age. Advanced tumour stages were associated with lower rates of SFRP1 gene methylation. Decreased methylation levels of the SFRP2 and RASSF1A genes were associated with positive N stage. On the contrary, lymph node metastasis were associated with higher methylation rates of RARβ and DAPK1 genes. Patients with a familial history of cancer were associated with more frequently methylated SFRP1, SFRP2 and DAPK1 genes. Hypermethylation of DAPK1 was associated with decreased risk of death in patients. Our results are suggestive, although not conclusive, that some epigenetic changes, especially frequent hypermethylation of SFRP2 and DAPK1 genes, can be useful as potential diagnostic biomarkers of oral cavity cancer. Moreover, estimating the methylation status in surgical margins could become an additional strategy for more accurate treatment methods. Further efforts are needed to identify and validate this finding on a larger patient group and using new advanced methylation testing methods.

Zeng X, Zhang Y, Xu H, et al.
Secreted Frizzled Related Protein 2 Modulates Epithelial-Mesenchymal Transition and Stemness via Wnt/β-Catenin Signaling in Choriocarcinoma.
Cell Physiol Biochem. 2018; 50(5):1815-1831 [PubMed] Related Publications
BACKGROUND/AIMS: Choriocarcinoma (CC) is a highly aggressive gestational trophoblastic neoplasia; however, the underlying molecular mechanisms of its invasiveness and metastasis remain poorly understood. Human secreted frizzled-related protein 2 (SFRP2) could function as a tumor promoter or suppressor in different tumors, yet the role it plays in CC's invasion and metastasis is thoroughly unclear. The current study was aimed to explore the function and underlying mechanism of SFRP2 in CC.
METHODS: The expression of SFRP2 in CC tissues was examined via immunohistochemistry. The methylation level and expression of SFRP2 in CC cell lines, JEG-3 and JAR were examined via bisulfite sequencing PCR (BSP), western blotting and quantitative RT-PCR. The biological role of increasing expressed SFRP2 through its promoter demethylation with 5-Aza-2'-deoxycytidine (5-Aza) was examined by a series of in vitro functional studies. Furthermore, lentivirus transfection technology was adopted to investigate the biological roles of SFRP2 knockdown in JEG-3 and JAR cells in vitro and in vivo. Moreover, its downstream signaling pathway was investigated.
RESULTS: SFRP2 was downregulated in CC tissues, and its expression was inversely related to its promoter hypermethylation frequency in JEG-3 and JAR cells. Increased SFRP2 through its promoter demethylation inhibited cell migration, invasion and colony formation in JEG-3 and JAR cells, whereas decreased SFRP2 reversed the epithelial-mesenchymal transition (EMT) process and stemness in JEG-3 and JAR cells both in vitro and vivo. Mechanistically, SFRP2 regulated the EMT and stemness of CC cell lines via canonical Wnt/β-catenin signaling, validated by the usage of a Wnt activator and inhibitor.
CONCLUSION: The current study indicates that downregulated SFRP2 has potent tumor-promotive effects in CC through the modulation of cancer stemness and the EMT phenotype via activation of Wnt/β-catenin signaling in vitro and in vivo.

Hu H, Wang T, Pan R, et al.
Hypermethylated Promoters of Secreted Frizzled-Related Protein Genes are Associated with Colorectal Cancer.
Pathol Oncol Res. 2019; 25(2):567-575 [PubMed] Related Publications
Colorectal cancer (CRC) is one of the leading causes of death worldwide. Aberrant DNA methylation has been recognized as one of the most common molecular alterations in CRC. The goal of this study was to investigate the diagnostic value of SFRP1 and SFRP2 methylation for CRC. A total of 80 pairs of CRC patients were recruited to test the association of SFRP1 and SFRP2 promotor methylation with CRC. Methylation assay was performed using quantitative methylation-specific polymerase chain reaction (qMSP) method. In this study, we found the methylation levels of SFRP1 and SFRP2 in CRC tumor tissues were significantly higher than those in the adjacent non-tumor tissues (SFRP1: P = 2E-5; SFRP2: P = 0.014). Further bioinformatics analysis of TCGA data confirmed the association of the two genes with CRC (SFRP1: P = 7E-21; SFRP2: P = 5E-24). Luciferase reporter gene assay showed that the recombinant plasmids with SFRP1 and SFRP2 fragments could significantly enhance promoter activity (SFRP1: P = 0.002; SFRP2: P = 0.004). In addition, SFRP1 and SFRP2 methylation were inversely correlated with the mRNA expression displayed by TCGA data mining (SFRP1: r = -0.432, P = 4E-11; SFRP2: r = -0.478, P = 1E-13). GEO data analysis indicated that SFRP1 and SFRP2 expression were increased in three CRC cell lines (COLO320, HCT116 and HT29) after 5'-AZA-deoxycytidine treatment, suggesting that DNA methylation played an important role in regulating gene expression of the two genes. Our results confirmed that promoter methylation of SFRP1 and SFRP2 contributed to the risk of CRC.

Stojanović N, Dekanić A, Paradžik M, et al.
Differential Effects of Integrin
Mol Pharmacol. 2018; 94(6):1334-1351 [PubMed] Related Publications
Low survival rates of patients with metastatic triple-negative breast cancer (TNBC) and melanoma, in which current therapies are ineffective, emphasize the need for new therapeutic approaches. Integrin

Le AV, Szaumkessel M, Tan TZ, et al.
DNA Methylation Profiling of Breast Cancer Cell Lines along the Epithelial Mesenchymal Spectrum-Implications for the Choice of Circulating Tumour DNA Methylation Markers.
Int J Mol Sci. 2018; 19(9) [PubMed] Free Access to Full Article Related Publications
(1) Background: Epithelial⁻mesenchymal plasticity (EMP) is a dynamic process whereby epithelial carcinoma cells reversibly acquire morphological and invasive characteristics typical of mesenchymal cells. Identifying the methylation differences between epithelial and mesenchymal states may assist in the identification of optimal DNA methylation biomarkers for the blood-based monitoring of cancer. (2) Methods: Methylation-sensitive high-resolution melting (MS-HRM) was used to examine the promoter methylation status of a panel of established and novel markers in a range of breast cancer cell lines spanning the epithelial⁻mesenchymal spectrum. Pyrosequencing was used to validate the MS-HRM results. (3) Results:

Chen WL, Wang XK, Wu W
Identification of ITGA3 as an Oncogene in Human Tongue Cancer via Integrated Bioinformatics Analysis.
Curr Med Sci. 2018; 38(4):714-720 [PubMed] Related Publications
Human tongue cancer (TC) is an aggressive malignancy with a very poor prognosis. There is an urgent need to elucidate the underlying molecular mechanisms involved in TC progression. mRNA expression profiles play a vital role in the exploration of cancer-related genes. Therefore, the purpose of our study was to identify the progression associated candidate genes of TC by bioinformatics analysis. Five microarray datasets of TC samples were downloaded from the Gene Expression Omnibus (GEO) database and the data of 133 TC patients were screened from The Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSC) database. The integrated analysis of five microarray datasets and the RNA sequencing data of TC samples in TCGA-HNSC was performed to obtain 1023 overlapping differentially expressed genes (DEGs) in TC and adjacent normal tissue (ANT) samples. Next, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted to enrich the significant pathways of the 1023 DEGs and PI3KAkt signaling pathway (P=0.011) was selected to be the candidate pathway. A total of 23 DEGs with |log2 fold change (FC)| ≥1.0 in phosphatidylinositol 3-kinase-serine/threonine kinase (PI3K-Akt) signaling pathway were subjected to survival analysis of 125 eligible TC samples in TCGA database, indicating increased integrin-α3 gene (ITGA3) expression was significantly associated with poorer prognosis. Taken together, our study suggested ITGA3 may facilitate the development of TC via activating PI3K-Akt signaling pathway.

Bhangu JS, Beer A, Mittlböck M, et al.
Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis.
Ann Surg. 2018; 268(5):894-902 [PubMed] Related Publications
BACKGROUND: Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC.
PATIENTS AND METHODS: Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9.
RESULTS: The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response.
CONCLUSION: Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.

Fan J, Zhang Y, Mu J, et al.
TET1 exerts its anti-tumor functions via demethylating DACT2 and SFRP2 to antagonize Wnt/β-catenin signaling pathway in nasopharyngeal carcinoma cells.
Clin Epigenetics. 2018; 10(1):103 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: TET1 is a tumor suppressor gene (TSG) that codes for ten-eleven translocation methyl cytosine dioxygenase1 (TET1) catalyzing the conversion of 5-methylcytosine to 5-hydroxy methyl cytosine as a first step of TSG demethylation. Its hypermethylation has been associated with cancer pathogenesis. However, whether TET1 plays any role in nasopharyngeal carcinoma (NPC) remains unclear. This study investigated the expression and methylation of TET1 in NPC and confirmed its role and mechanism as a TSG.
RESULTS: TET1 expression was downregulated in NPC tissues compared with nasal septum deviation tissues. Demethylation of TET1 in HONE1 and HNE1 cells restored its expression with downregulated methylation, implying that TET1 was silenced by promoter hypermethylation. Ectopic expression of TET1 suppressed the growth of NPC cells, induced apoptosis, arrested cell division in G0/G1 phase, and inhibited cell migration and invasion, confirming TET1 TSG activity. TET1 decreased the expression of nuclear β-catenin and downstream target genes. Furthermore, TET1 could cause Wnt antagonists (DACT2, SFRP2) promoter demethylation and restore its expression in NPC cells.
CONCLUSIONS: Collectively, we conclude that TET1 exerts its anti-tumor functions in NPC cells by suppressing Wnt/β-catenin signaling via demethylation of Wnt antagonists (DACT2 and SFRP2).

Mojtabanezhad Shariatpanahi A, Yassi M, Nouraie M, et al.
The importance of stool DNA methylation in colorectal cancer diagnosis: A meta-analysis.
PLoS One. 2018; 13(7):e0200735 [PubMed] Free Access to Full Article Related Publications
A large number of tumor-related methylated genes have been suggested to be of diagnostic and prognostic values for CRC when analyzed in patients' stool samples; however, reported sensitivities and specificities have been inconsistent and widely varied. This meta-analysis was conducted to assess the detection accuracy of stool DNA methylation assay in CRC, early stages of CRC (advanced adenoma, non-advanced adenomas) and hyperplastic polyps, separately. We searched MEDLINE, Web of Science, Scopus and Google Scholar databases until May 1, 2016. From 469 publications obtained in the initial literature search, 38 studies were included in the final analysis involving 4867 individuals. The true positive, false positive, true negative and false negative of a stool-based DNA methylation biomarker using all single-gene tests considering a certain gene; regardless of a specific gene were pooled and studied in different categories. The sensitivity of different genes in detecting different stages of CRC ranged from 0% to 100% and the specificities ranged from 73% to 100%. Our results elucidated that SFRP1 and SFRP2 methylation possessed promising accuracy for detection of not only CRC (DOR: 31.67; 95%CI, 12.31-81.49 and DOR: 35.36; 95%CI, 18.71-66.84, respectively) but also the early stages of cancer, adenoma (DOR: 19.72; 95%CI, 6.68-58.25 and DOR: 13.20; 95%CI, 6.01-28.00, respectively). Besides, NDRG4 could be also considered as a significant diagnostic marker gene in CRC (DOR: 24.37; 95%CI, 10.11-58.73) and VIM in adenoma (DOR: 15.21; 95%CI, 2.72-85.10). In conclusion, stool DNA hypermethylation assay based on the candidate genes SFRP1, SFRP2, NDRG4 and VIM could offer potential diagnostic value for CRC based on the findings of this meta-analysis.

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.

Strzelczyk JK, Krakowczyk Ł, Gołąbek K, Owczarek AJ
Expression profiles of selected genes in tumors and matched surgical margins in oral cavity cancer: Do we have to pay attention to the molecular analysis of the surgical margins?
Adv Clin Exp Med. 2018; 27(6):833-840 [PubMed] Related Publications
BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are associated with an interplay between genetics and the environment; they account for 3% of all diagnosed malignant tumors in men and 2% of those in women.
OBJECTIVES: The aim of the study was to analyze the significance of TIMP3, SFRP1, SFRP2, CDH1, RASSF1, RORA, and DAPK1 gene expression in head and neck squamous cell carcinoma tumors, and in matching surgical margin samples. We also analyzed the association between clinical parameters and the expression of the selected genes.
MATERIAL AND METHODS: Following surgical resection, 56 primary HNSCC tumors and matching surgical margin samples were collected from patients at the Clinic of Oncological and Reconstructive Surgery of Maria Skłodowska-Curie Memorial Cancer Center and the Institute of Oncology in Gliwice, Poland. The gene expression levels were analyzed by quantitative reverse transcription (qRT)-PCR.
RESULTS: SFRP1 gene expression was statistically significantly lower in the tumor samples than in the surgical margins (0.30 ±0.36 vs 0.62 ±0.36; p < 0.01). No correlation was found between gene expression and clinical parameters, except DAPK1, where low expression correlated with alcohol abuse (0.85 ±1.19 vs 1.97 ±3.22; p = 0.074). Moreover, patients with G3 grade tumors, i.e., poorly differentiated tumors, had significantly higher values of DAPK1 gene expression than the G1 (well-differentiated tumors) and G2 (moderately differentiated) groups.
CONCLUSIONS: There are many different reasons and concepts for altered gene expression in tumors and surgical margin tissue. Tumor heterogeneity and its microenvironment are undoubtedly linked to the biology of HNSCC. In order to understand specific tumor behavior and the microenvironment, further studies are needed. To find markers connected with cancer development and to provide insight into the earliest stages of cancer development, attention should also be focused on molecular analysis of the surgical margins.

Li Z, Yang L, Liu X, et al.
Long noncoding RNA MEG3 inhibits proliferation of chronic myeloid leukemia cells by sponging microRNA21.
Biomed Pharmacother. 2018; 104:181-192 [PubMed] Related Publications
The long noncoding RNA (lnc) maternally expressed 3 (MEG3) is downregulated in many types of cancers. However, the relationship between lncRNA MEG3, microRNA-21 (miR-21) and chronic myeloid leukemia (CML) blast crisis is unknown. This study examined bone marrow samples from 40 CML patients and 10 healthy donors. Proliferation and apoptosis assays, real-time polymerase chain reaction (PCR), bisulfite sequencing PCR, Western blotting, luciferase assay, RNA pull-down, RNA immunoprecipitation (RIP), co-immunoprecipitation (CoIP) and Chromatin immunoprecipitation (ChIP) were performed. We found that MEG3 and PTEN expression were down-regulated, whereas, MDM2, DNMT1 and miR-21 were up-regulated in the accelerated and blast phases of CML. Treated with 5-azacytidine decreased the level of MDM2, DNMT1 and miR21, but increased the level of MEG3 and PTEN. Overexpression of MEG3 and silencing the expression of miR-21 inhibited proliferation and induced apoptosis. MEG3 overexpression and silencing the expression of miR21 influence the levels of MMP-2, MMP-9, bcl-2 and Bax. MEG3 was able to interact with MDM2 and EZH2. MDM2 could interact with DNMT1 and PTEN. MYC and AKT can interact with EZH2. ChIP-seq showed that the promoter of KLF4 and SFRP2 interacts with DNMT1. In conclusion, lncRNA MEG3 and its target miR21 may serve as novel therapeutic targets for CML blast crisis; and demethylation drugs might also have potential clinical application in treating CML blast crisis.

Sa KD, Zhang X, Li XF, et al.
A miR-124/ITGA3 axis contributes to colorectal cancer metastasis by regulating anoikis susceptibility.
Biochem Biophys Res Commun. 2018; 501(3):758-764 [PubMed] Related Publications
Metastasis is the major cause for the death of patients with colorectal cancer (CRC). Anoikis resistance enhances the survival of cancer cells during systemic circulation, thereby facilitating secondary tumor formation in distant organs. miR-124 is a pleiotropically tumor suppressive small non-coding molecule. However, its role and mechanism in the regulation of cancer cell anoikis are still unknown. Here, we found that overexpression of miR-124 promotes anoikis of CRC cells in vitro and in vivo. In silico analysis and the experimental evidence supported that ITGA3 is a bona fide target of miR-124. Moreover, we identifies that ITGA3 plays a critical role in the regulation of anoikis sensitivity in CRC cells. Finally, our analysis in TCGA datasets demonstrates that high levels of ITGA3 are closely associated with poor prognosis in CRC patients. Collectively, we establish a functional link between miR-124 and anoikis susceptibility and provide that a miR-124/ITGA3 axis could be a potential target for the treatment of metastatic CRC.

Li Z, Luo J
Research on epigenetic mechanism of SFRP2 in advanced chronic myeloid leukemia.
Biochem Biophys Res Commun. 2018; 501(1):64-72 [PubMed] Related Publications
Secreted frizzled-related protein 2 (SFRP2) has been reported to act as a tumor suppressors. This study aims to detect the biological role of SFRP2 in advanced chronic myeloid leukemia (CML). In this study we examined bone marrow samples from 45 CML patients and 10 healthy donors. K562 and KCL22 cells were cultured and treated with demethylation drug and histone deacetylase inhibitor (HDACi). KCL22 and K562 cells were transfected with lentiviral vector (LV)-SFRP2, LV-control. The cells were then subjected to proliferation and apoptosis assays, real time polymerase chain reaction (PCR), Methylation-specific PCR (MSP), Western blotting, co-immunoprecipitation (CoIP) and Chromatin immunoprecipitation (ChIP), We found that SFRP2 was down-regulated in the accelerated and blast phase of CML, whereas, the levels of WNT1, WNT3 and WNT5A were up-regulated in the accelerated and blast phase of CML. Overexpression SFRP2 inhibited proliferation, promoted apoptosis and activated the WNT pathway. CoIP-MS results showed that SFRP2 interacted with WNT1 and WNT5A. ChIP-seq result indicated that the promoter of H3K4me3 and H3K27me3 were able to interact with SFRP2. In conclusion, our findings demonstrated the SFRP2 act as a potential therapeutic target for advanced CML. Furthermore, our results support the use of demethylation drugs and HDACi as a potential CML treatment strategy.

Ren J, Jian F, Jiang H, et al.
Decreased expression of SFRP2 promotes development of the pituitary corticotroph adenoma by upregulating Wnt signaling.
Int J Oncol. 2018; 52(6):1934-1946 [PubMed] Free Access to Full Article Related Publications
Cushing's disease is primarily caused by pituitary adrenocorticotropin‑secreting adenoma. However, its pathogenesis has remained obscure. In the present study, whole transcriptome analysis was performed by RNA sequencing (RNA‑Seq) and expression of secreted frizzled‑related protein 2 (SFRP2) was decreased in corticotroph tumors compared with normal pituitary glands. Furthermore, the RNA‑Seq results were validated and the expression of SFRP2 in tumor tissues was analyzed by comparing another cohort of 23 patients with Cushing's disease and 3 normal human pituitary samples using reverse transcription‑quantitative polymerase chain reaction, western blot and immunohistochemistry staining. Clinically, there was an association between lower SFRP2 expression and aggressive adenoma characteristics, including larger size and invasiveness. Conversely, SFRP2 overexpression reduced the ability of AtT20 cells to proliferate and migrate, and reduced production of the adrenocorticotrophic hormone in vitro. Mechanistically, overexpressed SFRP2 reduced the level of β‑catenin in the cytoplasm and nucleus, and decreased Wnt signaling activity in AtT20 cells. Therefore, SFRP2 appears to act as a tumor suppressor in Cushing's disease by regulating the activity of the Wnt signaling pathway.

Huang Y, Kong Y, Zhang L, et al.
High Expression of ITGA3 Promotes Proliferation and Cell Cycle Progression and Indicates Poor Prognosis in Intrahepatic Cholangiocarcinoma.
Biomed Res Int. 2018; 2018:2352139 [PubMed] Free Access to Full Article Related Publications
Integrin subunit alpha 3 (ITGA3) interacts with a beta 1 subunit to form a member of the integrin family. Integrins are heterodimeric integral membrane proteins that serve as cell surface adhesion proteins. In this research, we investigated the biological function of this protein in human intrahepatic cholangiocarcinoma (ICC) for the first time. Here, using Western blotting and immunohistochemistry assays, we discovered that ITGA3 was overexpressed in ICC cell lines and ICC patients. Moreover, we found ITGA3 expression correlated with several clinicopathological features, including tumor size, lymph node metastasis, and the TNM stage. Patients with high ITGA3 expression underwent a worse prognosis after complete resection compared with patients with low ITGA3 expression in terms of overall survival. Furthermore, we demonstrated that ITGA3 could significantly promote ICC cell proliferation and cell cycle progression

Pudova EA, Kudryavtseva AV, Fedorova MS, et al.
HK3 overexpression associated with epithelial-mesenchymal transition in colorectal cancer.
BMC Genomics. 2018; 19(Suppl 3):113 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Colorectal cancer (CRC) is a common cancer worldwide. The main cause of death in CRC includes tumor progression and metastasis. At molecular level, these processes may be triggered by epithelial-mesenchymal transition (EMT) and necessitates specific alterations in cell metabolism. Although several EMT-related metabolic changes have been described in CRC, the mechanism is still poorly understood.
RESULTS: Using CrossHub software, we analyzed RNA-Seq expression profile data of CRC derived from The Cancer Genome Atlas (TCGA) project. Correlation analysis between the change in the expression of genes involved in glycolysis and EMT was performed. We obtained the set of genes with significant correlation coefficients, which included 21 EMT-related genes and a single glycolytic gene, HK3. The mRNA level of these genes was measured in 78 paired colorectal cancer samples by quantitative polymerase chain reaction (qPCR). Upregulation of HK3 and deregulation of 11 genes (COL1A1, TWIST1, NFATC1, GLIPR2, SFPR1, FLNA, GREM1, SFRP2, ZEB2, SPP1, and RARRES1) involved in EMT were found. The results of correlation study showed that the expression of HK3 demonstrated a strong correlation with 7 of the 21 examined genes (ZEB2, GREM1, TGFB3, TGFB1, SNAI2, TWIST1, and COL1A1) in CRC.
CONCLUSIONS: Upregulation of HK3 is associated with EMT in CRC and may be a crucial metabolic adaptation for rapid proliferation, survival, and metastases of CRC cells.

Cheng YY, Mok E, Tan S, et al.
Dis Markers. 2017; 2017:2536187 [PubMed] Free Access to Full Article Related Publications
Malignant pleural mesothelioma (MPM) is associated with asbestos exposure. Asbestos can induce chronic inflammation which in turn can lead to silencing of tumour suppressor genes. Wnt signaling pathway can be affected by chronic inflammation and is aberrantly activated in many cancers including colon and MPM.

Zhang X, Rong X, Chen Y, Su L
Methylation-mediated loss of SFRP2 enhances invasiveness of non-small cell lung cancer cells.
Hum Exp Toxicol. 2018; 37(2):155-162 [PubMed] Related Publications
The malignancy of non-small cell lung cancer (NSCLC) largely results from its invasive manner. Secreted frizzled-related proteins (SFRPs) have been recently found to suppress the invasiveness of some cancers. On the other hand, the methylation of SFRPs increases protein degradation to reduce the activity of SFRPs, resulting in increased tumor cell invasion and cancer metastasis. However, the role of SFRPs in the invasion of NSCLC has not been reported. Here we analyzed the regulation of SFRPs in NSCLC cells and its effects on cell invasion. We found that SFRP2 mRNA was significantly decreased and methylation of SFRP2 gene was significantly increased in NSCLC tissue, compared to the paired adjacent nontumor tissue. Moreover, SFRP2 expression was significantly decreased in NSCLC cell lines. In NSCLC cell lines, the SFRP2 expression would be restored by the demethylation of SFRP2 gene with 5'-aza-deoxycytidine in NSCLC cell lines, at the levels of both mRNA and protein. Thus, the cell invasion would be suppressed. Furthermore, the demethylation of SFRP2 gene appeared to inhibit Zinc Finger E-Box Binding Homeobox 1 (ZEB1) and matrix metallopeptidase 9 (MMP9), two key factors that enhance NSCLC cell invasion. Thus, SFRP2 may inhibit NSCLC invasion by suppressing ZEB1 and MMP9, while its methylation promotes NSCLC invasion.

Liu G, Yan T, Li X, et al.
Daam1 activates RhoA to regulate Wnt5a‑induced glioblastoma cell invasion.
Oncol Rep. 2018; 39(2):465-472 [PubMed] Free Access to Full Article Related Publications
The signaling pathway of dishevelled-associated activator of morphogenesis 1 (Daam1) triggered by Wnt5a drives cell movement and migration during breast cancer metastasis. However, Wnt5a signaling in glioblastoma progression remains poorly defined. Wnt5a expression and activations of RhoA, Cdc42, and Rac1 were detected in human glioblastoma tissues by using ELISA assays and small G-protein activation assays, respectively. The cell invasion rate and Daam1 activation of glioblastoma U251 and T98MG cells were determined by cell invasion assays and pull-down assays, respectively. According to our experiments, Wnt5a expression and RhoA activation were upregulated in invasive glioblastoma tissues, with a significant positive correlation between them. Wnt5a activated Daam1 and RhoA, and subsequently promoted the invasion of glioblastoma U251 and T98MG cells. This process was abolished by secreted frizzled-related protein 2 (sFRP2), an antagonist that directly binds to Wnt5a. Specific small interfering RNA (siRNA) targeting Daam1 markedly inhibited Wnt5a-induced RhoA activation, stress fiber formation and glioblastoma cell invasion. CCG-1423, a RhoA inhibitor, decreased Wnt5a-induced stress fiber formation and glioblastoma cell invasion. Finally, siRNA targeting Daam1 or CCG-1423 treatment did not alter the cell proliferation of glioblastoma U251 and T98MG cells. We thus concluded that Wnt5a promoted glioblastoma cell invasion via Daam1/RhoA signaling pathway.

Carbone C, Piro G, Gaianigo N, et al.
Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling.
Int J Obes (Lond). 2018; 42(3):334-343 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions.
METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPO
CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.

Zou Y, Zheng M, Yang W, et al.
Virus-Mimicking Chimaeric Polymersomes Boost Targeted Cancer siRNA Therapy In Vivo.
Adv Mater. 2017; 29(42) [PubMed] Related Publications
Small interfering RNA (siRNA) offers a highly selective and effective pharmaceutical for various life-threatening diseases, including cancers. The clinical translation of siRNA is, however, challenged by its short plasma life, poor cell uptake, and cumbersome intracellular trafficking. Here, cNGQGEQc peptide-functionalized reversibly crosslinked chimaeric polymersomes (cNGQ/RCCPs) is shown to mediate high-efficiency targeted delivery of Polo-like kinase1 specific siRNA (siPLK1) to orthotopic human lung cancer in nude mice. Strikingly, siRNA is completely and tightly loaded into the aqueous lumen of the polymersomes at an unprecedentedly low N/P ratio of 0.45. cNGQ/RCCPs loaded with firefly luciferase specific siRNA (siGL3) or siPLK1 are efficiently taken up by α

Prichard DO, Byrne AM, Murphy JO, et al.
Deoxycholic acid promotes development of gastroesophageal reflux disease and Barrett's oesophagus by modulating integrin-αv trafficking.
J Cell Mol Med. 2017; 21(12):3612-3625 [PubMed] Free Access to Full Article Related Publications
The fundamental mechanisms underlying erosive oesophagitis and subsequent development of Barrett's oesophagus (BO) are poorly understood. Here, we investigated the contribution of specific components of the gastric refluxate on adhesion molecules involved in epithelial barrier maintenance. Cell line models of squamous epithelium (HET-1A) and BO (QH) were used to examine the effects of bile acids on cell adhesion to extracellular matrix proteins (Collagen, laminin, vitronectin, fibronectin) and expression of integrin ligands (α

Huang Q, Yang Q, Mo M, et al.
Screening of exon methylation biomarkers for colorectal cancer via LC-MS/MS strategy.
J Mass Spectrom. 2017; 52(12):860-866 [PubMed] Related Publications
The identification of biomarkers would be of benefit for the diagnosis and treatment of colorectal cancer. DNA methylation in specific genomic regions, which had shown strongly association with disease genotypes, was an effective indicator to reveal the occurrence and development of cancers. To screen out methylation biomarkers for colorectal cancer (CRC), genomic DNA was isolated from colorectal cancerous and corresponding cancer-adjacent tissues collected from 30 CRC patients and then bisulfite-converted. The exon regions of 5 targeted genes (CNRIP1, HIC1, RUNX3, p15, and SFRP2) were amplified by using nested polymerase chain reaction with specific primers, and the amplicon was purified and hydrolyzed. The methylation levels of these specific regions were detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). The results showed that 5 targeted exon regions were successfully amplified and confirmed by sequencing. The methodological validations indicated that LC-MS/MS was highly sensitive and accurate. The methylation levels of CNRIP1 and RUNX3 were remarkably high in CRC tissues with statistical difference when compared with corresponding cancer-adjacent individuals, while that of HIC1, p15, and SFRP2 had no difference between 2 subjects. These findings supported CNRIP1 and RUNX3 as potential DNA methylation biomarkers for CRC diagnosis and treatment, and our LC-MS/MS approach exhibited great advantages in the identification of regional DNA methylation biomarkers.

Duan H, Yan Z, Chen W, et al.
TET1 inhibits EMT of ovarian cancer cells through activating Wnt/β-catenin signaling inhibitors DKK1 and SFRP2.
Gynecol Oncol. 2017; 147(2):408-417 [PubMed] Related Publications
OBJECTIVE: Epithelial ovarian cancer (EOC) is the deadliest type of ovarian cancer, but the mechanisms contributing to its tumorigenesis are not well understood. Herein, we will elucidate the role of Ten-eleven translocation 1 (TET1) in EOC development.
METHODS: The expression of TET1 in EOC cell lines and primary samples was examined by western blot and immunohistochemistry. The biological role of ectopic TET1 overexpression was revealed by a series of in vitro functional studies. Its downstream signaling pathway was predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of microarray data. The methylation level and expression of Wnt/β-catenin signaling inhibitors Dikkopf 1 (DKK1) and secreted Fzd receptor protein 2 (SFRP2) were examined by Chromatin immunoprecipitation (ChIP) assay, Epimark™ 5hmC and 5mC level analysis and quantitative RT-PCR. Small interference RNA (siRNA) technology was used to investigate the biological roles of DKK1 and SFRP2.
RESULTS: TET1 expression was inversely correlated with clinical stage in patients with EOC by tissue microarray (TMA). TET1 expression was undetected in 6 types of EOC cell lines. Ectopic expression of TET1 inhibited colony formation, cell migration and invasion in SKOV3 and OVCAR3 cells. Furthermore, TET1 overexpression reversed the epithelial-mesenchymal transition (EMT) process of SKOV3 cells. Mechanistically, TET1 potently inhibited canonical Wnt/β-catenin signaling by demethylating and upregulating two upstream antagonists of this pathway, SFRP2 and DKK1, which was associated with inhibition of EMT and cancer cell metastasis.
CONCLUSION: This study uncovers that TET1 has potent tumor-suppressive effects in EOC by activating Wnt/β-catenin signaling inhibitors DKK1 and SFRP2.

Kriegshäuser G, Enko D, Zitt M, et al.
Comparison of a prototype reverse hybridization assay and MethyLight for detection of SFRP2 promotor methylation in fecal DNA.
Int J Biol Markers. 2017; 32(4):e467-e470 [PubMed] Related Publications
BACKGROUND: This study aimed to evaluate the diagnostic performance of a novel nonquantitative methylation-specific reverse hybridization (MSRH) assay to detect secreted frizzled-related protein 2 (SFRP2) promotor methylation in fecal DNA.
METHODS: SFRP2 promoter methylation was investigated in stool DNA isolated from 18 colorectal cancer (CRC) patients and 22 healthy controls using the MSRH assay based on methylation-specific DNA amplification followed by reverse hybridization of biotinylated amplicons to sequence-specific methylation detection probes, with MethyLight serving as a reference method.
RESULTS: SFRP2 promotor methylation as determined by MSRH vs. MethyLight showed a sensitivity and specificity of 61.1% and 86.3% vs. 77.7% and 77.3%, respectively. Moderate agreement (ĸ = 0.54, 95% confidence interval [95% CI], 0.29-0.80, p<0.001) was observed between the 2 methods. However, the differences in SFRP2 promotor methylation observed between CRC patients and healthy individuals by both assays were statistically significant (p<0.001).
CONCLUSIONS: Our findings, although limited by the small sample size, do not support the use of the MSRH assay for CRC screening in stool.

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