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Involvement of key modulators of Wnt signaling, sFRP1 and sFRP3, across malignancy grades of human astrocytoma

SFRP gene family code for important regulatory proteins of Wnt signaling usually limiting pathway’s activity. We investigated the involvement of SFRP1 and SFRP3 in astrocytomas of different malignancy grades in order to better understand their behavior in tumor progression. The expression was analyzed by immunohistochemistry, digital scanning and image analysis. Promoter hypermethylation was examined with methylation-specific polymerase-chain- reaction. Our results demonstrate that hypermethylation of SFRP1 promoter was progressively rising in astrocytoma grades with the highest distribution in glioblastoma (P=0.042). Furthermore, cases with methylated promoter expressed significantly less SFRP1 than unmethylated ones (P=0.031). Pathway’s indicators of oncogenic activity, beta-catenin, LEF1 and TCF1, were also explored. Glioblastomas with unmethylated SFRP1 promoter had significantly less beta-catenin (P=0.033), while strong expression of both LEF1 and TCF1 was associated to higher astrocytoma grades (P=0.006). The results on SFRP3 involvement were not so straightforward demonstrating different behavior in subcellular compartments. Stronger nuclear expression values were associated with lower astrocytomas grades (P=0.028) as compared with astrocytoma grades III and IV. Contrary, stronger cytoplasmic expression levels were higher in the astrocytoma III and IV group than in the astrocytoma I and II group (P=0.048). Our findings show that SFRP1 gene behaves as a classical tumor suppressor and was significantly epigenetically silenced in glioblastomas as compared to low astrocytoma grades, suggesting its lack allows progression. SFRP3 protein demonstrated dual behavior as an antagonist of Wnt signaling when found in the nucleus, whereas when located in the cytoplasm as an agonist of Wnt signaling promoting invasive behavior.

Wnt signaling pathway ; sFRP1 ; sFRP3 ; astrocytomas

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