engleski

Key components of Wnt signaling are changed across different malignancy grades of astrocytoma

Astrocytomas are the most common primary tumors of the central nervous system. According to the WHO classification, there are four grades of astrocytoma, considering their histology, molecular characteristics and prognosis. The aim of this study was to investigate changes in gene structure and protein expression of Dishevelled family and transcription factors TCF1 and LEF1, molecular components of the Wnt signaling pathway, in 80 astrocytic brain tumors and compare results with clinical parameters. Genetic changes were analyzed by PCR/LOH/MSI method by using polymorphic microsatellite markers D1S468 and D1S243 for DVL1, D1S17960 for DVL2 and D3S1262 for DVL3 gene. Protein expression and localization were examined by immunohistochemistry. Four selected microsatellite markers have shown a significant number of samples demonstrating MSI and LOH, genetic changes that contribute to the genome instability in cancer. Diffuse astrocytomas (WHO grade II) analyzed with D1S468 (p=0.008) showed the highest percentage of MSI (70%), while LOH was the most common in glioblastoma (31.2%) analyzed with D3S1262. The results obtained on the total sample indicate that the microsatellite instability is constantly present, with a more frequent appearance in lower grades and may be the cause of astrocytoma formation, whereas large deletions are significantly associated with the highest grade and have a role in progression. The levels of DVL1, DVL2 and DVL3 protein expression did not show statistically significant correlation with genetic changes. Nevertheless, statistically significant differences in the number of cells with certain level of expression of a single protein between the grades were observed. 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). DVL1 was also negatively correlated (p<0.001) with astrocytoma grade, while DVL3 (p<0.001), TCF1 (p=0.008) and LEF1 (p<0.001) showed positive correlation with malignancy grade suggesting involvement of these proteins in malignant progression. These results contribute to a better understanding of the molecular profile of astrocytic brain tumors and could serve as molecular markers of progression.

Wnt signaling, astrocytoma

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