Secreted Frizzled-related Protein 4 Expression Research Articles

Secreted frizzled-related protein 4 and its implications in cancer and apoptosis.

Secreted frizzled-related protein 4 (SFRP4) is a glycoprotein that acts as an antagonist of Wnt ligands, causing inhibition of the canonical Wnt signalling pathway. First noticed due to high expression levels during times of increased apoptosis, SFRP4 has been implicated in cell proliferation and differentiation and plays an important role in carcinogenesis. Many tumours such as endometrial, cervical, ovarian, prostate, bladder, colorectal, mesothelioma, pancreatic, renal, and oesophageal tumours are characterised by aberrant promoter hypermethylation, which causes variations in the expression level of SFRP4 when compared to normal cells. Combined experimental data appear to confirm the suggested role of SFRP4 as a local initiator of apoptosis; however, increased SFRP4 expression may not always correlate with an increase in apoptosis, possibly due to the complex interactions between different signalling pathways. SFRP4 can be explored for its use in novel therapeutic modalities as well as being a potential diagnostic biomarker.

MicroRNA-152 modulates the canonical Wnt pathway activation by targeting DNA methyltransferase 1 in arthritic rat model.

Rheumatoid arthritis (RA) is an autoimmune and progressive systemic disease of unknown etiology. Research shows that fibroblast-like synoviocytes (FLS) participate in the cartilage erosion, synovial hyperplasia, inflammatory cytokine secretion and suggests that fibroblast-like synoviocytes (FLS) display a crucial role in RA pathogenesis. Recent studies have suggested the role of the Wnt signaling pathway in the pathogenesis of RA. In previous study, we identified that increased methyl-CpG-binding protein 2 (MeCP2) reduced the secreted frizzled-related protein 4 (SFRP4) expression in FLS in Arthritic rat model and the DNA methyltransferase (DNMT) inhibitor 5-Aza-2'-deoxycytidine (5-azadC) could induce the SFRP4 expression, indicating that DNMT has a key role in the differential expression of SFRP4. MicroRNAs (MiRNAs), which are small non-coding RNAs, are involved in diverse biological functions, regulation of gene expression, pathogenesis of autoimmune disease and carcinogenesis. In light of the directly down-regulation of miR-152 on DNMT1 expression by targeting the 3' untranslated regions of its transcript in nickel sulfide (NiS)-transformed human bronchial epithelial cells, we investigated whether miR-152 is aberrantly expressed and targets DNMT1 in FLS in Arthritic rat model. Our results demonstrated that the expression of miR-152 was specifically down-regulated in Arthritic rat model, whereas up-regulation of miR-152 in FLS resulted in a marked reduction of DNMT1 expression. Further experiments revealed that increased miR-152 indirectly up-regulated the SFRP4 expression, a negative regulator of WNT signaling pathway, by targeting the DNMT1. Moreover, activation of miR-152 expression in FLS could inhibit the canonical Wnt pathway activation and result in a significant decrease of FLS proliferation. MiR-152 and DNA methylation may provide molecular mechanisms for the activation of canonical Wnt pathway in RA. Combination of miR-152 and DNMT1 may be a promising treatment strategy for RA patients in which SFRP4 is inactivated.

Chuju total flavonoids control the SFRP4 expression in Wnt pathway in rheumatoid arthritis model rats

To determine the effect of Chuju total flavonoids (CJTF) on the secreted frizzledrelated protein 4 (SFRP4) expression in Wnt pathway in rheumatoid arthritis (RA) model rats. The role of CJTF in the treatment of RA model rats was evaluated by rat arthritis score and paw edema score. The expression regulation of the SFRP4, β-catenin and C-myc in Wnt pathway in RA model rats was detected by RT-PCR and Western blot after CJTF gavage treatment. After CJTF treatment, the rat arthritis score and paw edema score in RA model rats were significantly decreased when the RA model rats were treated with CJTF, the SFRP4 expression was significantly up-regulated, while the β-catenin and C-myc gene expression were significantly downregulated in RA model rat synovial tissues. CJTF has significant therapeutic effect and inhibitory effect on Wnt pathway activation by targeting SFRP4 in RA model rat synovium.

THU0030 Evidence for good intrinsic mesenchymal stem cell activity in gelatinous heberden’s nodes in osteoarthritis at clinical presentation

BackgroundHeberden’s nodes (HN) are common pre-radiographic features of generalised osteoarthritis (GOA) and they may present as acute cystic lesions before eventually leading to florid new bone formation [1].ObjectivesTo examine if...

MeCP2 modulates the canonical Wnt pathway activation by targeting SFRP4 in rheumatoid arthritis fibroblast-like synoviocytes in rats

Rheumatoid arthritis (RA) is an autoimmune disease characterized by the rheumatoid factor and anti-citrullinated peptide antibody (ACPA) against common autoantigens that are widely expressed within and outside the joints. Many factors participate in the pathogenesis of RA, such as cytokine imbalance, Wnt pathway activation, matrix production, and osteoprotegerin on osteoclasts. Fibroblast-like synoviocytes (FLS) activation has an important role in RA pathogenesis. The methyl-CpG-binding protein (MeCP2) which promoted repressed chromatin structure was selectively detected in synovium of diseased articular in rats. Overexpression of this protein results in an up-regulation of global methylation levels and transcriptional suppression of specific genes. There were increased MeCP2 and decreased secreted frizzled-related protein 4 (SFRP4) in synovium as well as the FLS isolated from the synovium of RA rats. Knockdown of MeCP2 using siRNA technique enhanced SFRP4 expression in both mRNA and protein levels in FLS. These results indicated that epigenetic modification was involved in differential expression of SFRP4. To further explore the underlying molecular mechanisms, we hypothesized that the SFRP4 down-regulation in synovium was caused by DNA methylation. Treatment of FLS with DNA methylation inhibitor 5-Aza-2′-deoxycytidine (5-azadC) blocked the cell proliferation and increased the SFRP4 expression. Increased SFRP4 down-regulated the key gene β-catenin, the downstream effectors gene ccnd1 and fibronectin expression in canonical Wnt pathway at the same time. MeCP2 and DNA methylation may provide molecular mechanisms for canonical Wnt pathway activation in RA. Combination of 5-azadC and MeCP2 may be a promising treatment strategy for individuals with RA in which SFRP4 is inactivated.

Estrogens and selective estrogen receptor modulators regulate gene and protein expression in the mesenteric arteries

Estrogen has both beneficial and detrimental effects on the cardiovascular system. Selective estrogen receptor modulators (SERMs) exhibit partial estrogen agonist/antagonist activity in estrogen target tissues. Gene targets of estrogen and SERMs in the vasculature are not well-known. Thus, the present study tested the hypothesis that estrogens (ethinyl estradiol, estradiol benzoate, and equilin) and SERMs (tamoxifen and raloxifene) cause differential gene and protein expression in the vasculature. DNA microarray and real-time RT-PCR were used to investigate gene expression in the mesenteric arteries of estrogen and SERM treated ovariectomized rats. The genes shown to be differentially expressed included stearoyl-CoA desaturase (SCD), soluble epoxide hydrolase (sEH), secreted frizzled related protein-4 (SFRP-4), insulin-like growth factor-1 (IGF-1), phospholipase A2 group 1B (PLA2-G1B), and fatty acid synthase (FAS). Western blot further confirmed the differential expression of sEH, SFRP-4, FAS, and SCD protein. These results reveal that estrogens and SERMs cause differential gene and protein expression in the mesenteric artery. Consequently, the use of these agents may be associated with a unique profile of functional and structural changes in the mesenteric arterial circulation.

Secreted Frizzled-Related Protein 4 Regulates Two Wnt7a Signaling Pathways and Inhibits Proliferation in Endometrial Cancer Cells

In the endometrium, hormonal effects on epithelial cells are often elicited through stromal hormone receptors via unknown paracrine mechanisms. Several lines of evidence support the hypothesis that Wnts participate in stromal-epithelial cell communication. Wnt7a is expressed in the luminal epithelium, whereas the extracellular modulator of Wnt signaling, secreted frizzled-related protein 4 (SFRP4), is localized to the stroma. Studies have reported that SFRP4 expression is significantly decreased in endometrial carcinoma and that both SFRP4 and Wnt7a genes are differentially regulated in response to estrogenic stimuli. Aberrant Wnt7a signaling irrevocably causes organ defects and infertility and contributes to the onset of disease. However, specific frizzled receptors (Fzd) that bind Wnt7a and the particular signal transduction pathway each Wnt7a-Fzd pair activates have not been identified. Additionally, the function of SFRP4 in the endometrium has not been addressed. We show here that Wnt7a coimmunoprecipitates with Fzd5, Fzd10, and SFRP4 in Ishikawa cells. Wnt7a binding to Fzd5 was shown to activate beta-catenin/canonical Wnt signaling and increase cellular proliferation. Conversely, Wnt7a signaling mediated by Fzd10 induced a noncanonical c-Jun NH2-terminal kinase-responsive pathway. SFRP4 suppresses activation of Wnt7a signaling in both an autocrine and paracrine manner. Stable overexpression of SFRP4 and treatment with recombinant SFRP4 protein inhibited endometrial cancer cell growth in vitro. These findings support a mechanism by which the nature of the Wnt7a signal in the endometrium is dependent on the Fzd repertoire of the cell and can be regulated by SFRP4.

Inverse correlation of secreted frizzled-related protein 4 and beta-catenin expression in endometrial stromal sarcomas.

Endometrial stromal sarcomas are rare uterine tumours. Whereas the histology and immunohistochemistry of these tumours are well documented, almost nothing is known about the molecular mechanisms involved in their pathogenesis. To characterize the genes altered in these malignancies, a genome-wide cDNA library was generated by suppression subtractive hybridization and a set of differentially expressed clones was isolated. These were then used to produce custom-spotted cDNA arrays. Genes deregulated in endometrial stromal sarcomas were identified by cDNA array hybridization and were confirmed by quantitative real-time PCR analyses and in situ hybridization. Following cDNA array analysis, more than 300 genes deregulated in endometrial stromal sarcoma were selected and sequenced. Among the most significantly deregulated genes were those of secreted frizzled-related proteins (SFRPs), in particular secreted frizzled-related protein 4 (SFRP4). SFRPs are putative modulators of the Wnt-signalling pathway and play a role in different cellular events including cell proliferation. Compared with normal endometrium, the expression of SFRP4 was decreased in both low-grade endometrial stromal sarcoma (ESS; n = 10) and undifferentiated endometrial sarcoma (UES; n = 4), being lower in the latter more aggressive form. These results were verified on paraffin wax-embedded tissue by quantitative real-time PCR analysis and in situ hybridization. Furthermore, the expression of beta-catenin, an important component of the Wnt-signalling pathway, was regulated in an opposite manner to SFRP4, being particularly increased in undifferentiated sarcomas. The activation of the Wnt-signalling pathway was additionally supported by the immunohistochemical demonstration that beta-catenin was translocated to the nucleus in UES. SFRP4 may therefore be a putative tumour suppressor involved in deregulation of the Wnt pathway and in the pathogenesis of ESS and UES.