Expression patterns of Wnt signaling component, secreted frizzled-related protein 3 in astrocytoma and glioblastoma

Abstract

Secreted frizzled-related protein 3 (SFRP3) is a member of the family of soluble proteins, which modulate the Wnt signaling cascade. Novel research has identified aberrant expression of SFRPs in different types of cancer. In the present study the expression intensities and localizations of the SFRP3 protein across different histopathological grades of astrocytic brain tumors were investigated by immunohistochemistry, digital scanning and image analysis. The results demonstrated that the differences between expression levels and malignancy grades were statistically significant. Tumors were classified into four malignancy grades according to the World Health Organization guidelines. Moderate (P=0.014) and strong (P=0.028) nuclear expression levels were significantly different in pilocytic (grade I) and diffuse (grade II) astrocytomas demonstrating higher expression values, as compared with anaplastic astrocytoma (grade III) and glioblastoma (grade IV). When the sample was divided into two groups, the moderate and high cytoplasmic expression levels were observed to be significantly higher in glioblastomas than in the group comprising astrocytoma II and III. Furthermore, the results indicated that high grade tumors were associated with lower values of moderate (P=0.002) and strong (P=0.018) nuclear expression in comparison to low grade tumors. Analysis of cytoplasmic staining demonstrated that strong cytoplasmic expression was significantly higher in the astrocytoma III and IV group than in the astrocytoma I and II group (P=0.048). Furthermore, lower grade astrocytomas exhibited reduced membranous SFRP3 staining when compared with higher grade astrocytomas and this difference was statistically significant (P=0.036). The present results demonstrated that SFRP3 protein expression levels were decreased in the nucleus in higher grade astrocytoma (indicating the expected behavior of an antagonist of Wnt signaling), whereas when the SFRP3 was located in the cytoplasm an increased expression level of SFRP3 was identified in the high grade astrocytomas when compared with those of a low grade. This may suggest that SFRP3 acts as an agonist of Wnt signaling and promotes invasive behavior.

SFRP5 serves a beneficial role in arterial aging by inhibiting the proliferation, migration and inflammation of smooth muscle cells

“…β-catenin stabilization results in β-catenin translocation into the nucleus, followed by increased expression of proliferation-related genes (23). As SFRPs and Wnt proteins exhibit high homology in their cysteine-rich domains, SFRPs, including SFRP5, can compete with the frizzled receptor to bind Wnt ligands and regulate the canonical and non-canonical Wnt signaling pathways (24)(25)(26). In the present study, it was observed that SFRP5 attenuated β-catenin expression in SMCs.…”

Different behaviour of DVL1, DVL2, DVL3 in astrocytoma malignancy grades and their association to TCF1 and LEF1 upregulation

“…Therefore, the identification of novel molecular targets responsible for tumour progression and biomarkers for prediction of disease outcome and response to treatment is extremely requisite. Several novel studies indicate the involvement of Wnt signalling in the molecular pathogenesis of glial tumours . However, very little is known about the possible association of the proteins involved in the Wnt pathway with tumour malignancy.…”

“…Although it is still not possible to define the exact number and chronology of changes during gliomagenesis, they found that key genes responsible for the formation and progression of astrocytic brain tumours are most frequently involved into deregulated oncogenic pathways: RTK/RAS/PI3K, TP53 and RB . Recent studies have shown that altered signal transduction in Wnt signalling pathway is also involved in the molecular pathogenesis of glial tumours …”

Daam1 activates RhoA to regulate Wnt5a‑induced glioblastoma cell invasion

“…These results demonstrated that sFRP2 acted as an antagonist of Wnt5a mediating the progression of glioblastoma and breast cancer. A recent study in immunohistochemistry revealed that the expression level of soluble frizzled-related protein 3 (sFRP3) was decreased in the nucleus in higher grade astrocytoma, indicating the antagonistic ability of Wnt signaling ( 34 ). Further studies are needed to decipher whether sFRP2 and sFRP3 function in a common pathway or in parallel pathways to block Wnt5a signaling.…”