Membranous Expression of Secreted Frizzled-Related Protein 4 Predicts for Good Prognosis in Localized Prostate Cancer and Inhibits PC3 Cellular Proliferation in Vitro

Abstract

Purpose: Activation of the Wnt-signaling pathway is implicated in aberrant cellular proliferation in a variety of cancers. Secreted frizzled-related protein 4 (sFRP4) is a secreted protein with putative inhibitory activity of the Wntsignaling cascade through binding and sequestering Wnt ligands. Because sFRP4 mRNA is overexpressed in prostate cancers (PCs), the aim of this study was to define the pattern of sFRP4 protein expression in normal and malignant human prostate tissue and to determine whether changes in expression were associated with disease progression and prognosis, as well as to define the phenotype of sFRP4-overexpression in an in vitro model of PC.Experimental Design: Polyclonal antibodies were raised against a COOH-terminal peptide of sFRP4, characterized and used to assess sFRP4 protein expression in benign prostate tissue and 229 patients with clinically localized PC (median follow-up 77 months, range 1-156). In vitro studies of the function of sFRP4 overexpression were performed using PC3 cells transfected with sFRP4.Results: Benign and malignant prostate tissue demonstrated cytoplasmic sFRP4 immunoreactivity, but there was a decrease in the expression of membranous sFRP4 in PCs compared with the hyperplastic lesions (P < 0.0001). Kaplan-Meier analysis revealed that patients whose PC expressed membranous sFRP4 in >20% of cells had improved relapse-free survival compared with those with <20% membranous expression (P ‫؍‬ 0.002). Moreover, membranous sFRP4 expression (P ‫؍‬ 0.04) was an independent predictor of relapse when modeled with Gleason score (P ‫؍‬ 0.006), pathological stage (P ‫؍‬ 0.002), and pre-operative prostatespecific antigen levels (P ‫؍‬ 0.004). In addition, in vitro studies demonstrated a decrease in the proliferation rate of PC3 cells transfected with sFRP4 when compared with the control PC3-empty vector cells (P < 0.0001). Decreased levels of phosphorylated glycogen synthase kinase 3␤ in PC3-sFRP4 cells suggested that this phenotype is mediated by the "Wnt/␤-catenin" pathway.Conclusions: These data suggest that sFRP4 expression may be prognostic for localized PC, potentially as a consequence of an inhibitory effect on PC cell proliferation.

Aberrant methylation of secreted frizzled‐related protein genes in esophageal adenocarcinoma and Barrett's esophagus

“…40,41 This observation suggests that SFRP expression is lost progressively during the transition from normal epithelium to Barrett's esophagus and then to invasive cancer.…”

Differential gene expression in the peripheral zone compared to the transition zone of the human prostate gland

“…However, SFRP4 was actually downregulated in the exon array but the literature reports that this is overexpressed in CaP. 28 Marked differences in intra-individual gene expression patterns in the PZ compared to the TZ were observed (Table 4). Of note was the observation that many of these differentially expressed genes have previously been associated with cell growth and division, differentiation and cell migration.…”

Epigenetic Deregulation Across Chromosome 2q14.2 Differentiates Normal from Prostate Cancer and Provides a Regional Panel of Novel DNA Methylation Cancer Biomarkers

“…Kaplan-Meier and log-rank analyses evaluating disease relapse were performed. Further survival analysis was performed using univariate and multivariate analyses in a Cox proportional hazards model for GSTP1 status and other clinical and pathologic predictors of outcome as previously described (37). The multivariate model was produced by assessing GSTP1 status with other baseline covariates of clinical relevance such as Gleason grade, pathologic stage, and preoperative PSA, which were modeled as dichotomous or continuous variables as appropriate.…”