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Membranous Expression of Secreted Frizzled-Related Protein 4 Predicts for Good Prognosis in Localized Prostate Cancer and Inhibits PC3 Cellular Proliferation in Vitro
Ist Teil von
Clinical cancer research, 2004-01, Vol.10 (2), p.615-625
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
2004
Quelle
MEDLINE
Beschreibungen/Notizen
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 Wnt-signaling 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 prostate-specific 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 3β in PC3-sFRP4 cells suggested that this phenotype
is mediated by the “Wnt/β-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.