engleski

Wnt signalosome is targeted in astrocytoma

Wnt signaling pathway plays critical roles in development but also in adult tissue homeostasis, while its abnormal activation is causative for many cancers. Effectors of Wnt signaling: beta- catenin (CTNNB1), AXIN1, DVL1, DVL2, DVL3, TCF1, LEF1, SFRP1 and SFRP3, were investigated in astrocytomas of different malignancy grades. Those most common primary tumors of the central nervous system are classified by WHO into four grades, considering their histology, molecular characteristics and prognosis. PCR/LOH/MSI methods, employing polymorphic microsatellite markers, were used for assessing genetic changes, while protein expressions and localizations were examined by immunohistochemistry. Beta-catenin was upregulated in 50% of glioblastomas and 56% of astrocytomas, while its nuclear location was observed in 52.1% of glioblastomas. AXIN1 was down-regulated in 31% of glioblastomas and 22% of astrocytomas, while LOH of the gene was found only in 10% of glioblastomas. LOHs at all three DVL loci were more frequent in high-grade tumors, especially DVL3 (P=0.007) whose expression also significantly increased with malignancy grade (P<0.001). Contrary, DVL1 expression was downregulated in high-grade tumors (P<0.001). Transcription factors of the pathway, TCF1 and LEF1, were both significantly upregulated. Bivariate correlation of all analyzed proteins showed a statistically significant positive correlation between DVL3 and TCF1 (p=0.020), DVL3 and LEF1 (p=0.006), TCF1 and LEF1 (p=0.021), while DVL1 and DVL3 were negatively correlated (p=0.002). DVL3 (p<0.001), TCF1 (p=0.008) and LEF1 (p<0.001) all showed positive correlation increasing with astrocytoma grades suggesting involvement in malignant progression. Modulators of Wnt signaling, SFRP1 and SFRP3, showed opposing roles. SFRP1 gene was epigenetically silenced in glioblastomas when compared to lower grades (P=0.042), while SFRP3 cytoplasmic expression increased in higher grades. Taken together, our findings reveal important biomarkers influencing astrocytoma prognosis and contribute to a better understanding of its molecular profile.

Wnt signaling pathway ; astrocytoma ; DVL ; TCF1 ; LEF1 ; SFRP1 ; SFRP3

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