engleski

Wnt signalling effectors are targeted in astrocytoma

Wnt signalling builds a complex molecular network within the cell and maintains homeostasis by regulating cell survival, proliferation and migration. The malfunctioning of this pathway has repeatedly been implicated in tumorigenesis. The pathway is activated when beta-catenin accumulates in the cytoplasm and transfers to the nucleus where it binds to the transcription cofactors and activates proliferation programs. Effectors of Wnt signalling: beta-catenin (CTNNB1), AXIN1, DVL1, DVL2, DVL3, TCF1, LEF1, SFRP1 and SFRP3, in astrocytomas of different malignancy grades were investigated. 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 downregulated 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 tumours, especially DVL3 (P = 0.007) whose expression also significantly increased with malignancy grades (P < 0.001). Contrary, DVL1 expression was downregulated in high-grade tumours (P < 0.001). Transcription factors of the pathway, TCF1 and LEF1, were both significantly upregulated increasing with astrocytoma grades (P = 0.001). A positive correlation was established between DVL3 and both TCF1 (P = 0.020) and LEF1 (P = 0.006) suggesting their joint involvement in malignant progression. Modulators of Wnt signalling, 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. Our results promote the understanding of Wnt signalling in astrocytoma progression. The ongoing research could help in providing new molecular markers and treatment modalities.

Wnt signaling ; astrocytoma ; DVL3 ; beta-catenin ; LEF1

nije evidentirano