engleski

Key Wnt signalling molecules as potential biomarkers of astrocytic brain tumors

Wnt pathway has been established as one of the basic signalling pathways whose misregulation often governs tumorigenesis. Astrocytic brain tumors are classified according to their lineage of origin and behavior into four WHO grades. In spite of recent progress on the elucidation of astocytoma genetics, molecular mechanisms responsible for their formation and progression are still inadequately explained. In the present study key players of Wnt signaling: beta-catenin (CTNNB1), TCF1 and LEF1, Secreted frizzled‑related protein 3 (SFRP3) and disheveled-1 (DVL1) were investigated. Gene changes were tested by polymerase chain reaction/loss of heterozygosity (LOH) using RFLP and MSI analyses, and proteins expression by immuno histochemistry, digital scanning and image analysis. Our results demonstrated that 50% of glioblastomas (grade IV) and 56% of astrocytomas (grades II and III) showed upregulation of beta-catenin. Its nuclear localization which is an indicator of pathway's activation was found in 52.1% of cases. Furthermore, transcription factors of the Wnt pathway were also upregulated. Strong TCF1 and LEF1 expression was observed in 51.6% and 71% of glioblastomas. Astrocytoma grade I showed almost opposite expression levels with weak or no expression in the 63.2% for TCF-1 and 68.2% for LEF-1. The F–ratios for two variables (LEF1 strong and LEF1 weak) indicated that differences between astrocytomas (II, III) and glioblastomas were statistically significant (p<0.02). Discriminant function analysis further showed that just one variable –the strong expression of LEF-1, emerged to discriminate between astrocytomas and glioblastomas. This suggests that LEF-1 may serve as potential diagnostic marker. We have also demonstrated that SFRP3 nuclear expression levels, both moderate (P=0.002) and strong (P=0.018), were decreased in higher grade astrocytomas in comparison to low grade indicating the expected behavior of an antagonist of Wnt signalling. Whereas, when located in the cytoplasm an increased expression of SFRP3 was identified in the high grade astrocytomas (P=0.048). This may suggest that SFRP3 can also acts as an agonist of Wnt signaling and promote invasive behavior. Our findings contribute to better understanding of human astrocytic brain tumor genetic profile and suggest that Wnt signaling plays important role in its etiology. The findings may provide molecular biomarkers that will help in diagnostics and therapeutic decision-making.

Astrocytic brain tumors, Wnt signaling pathway

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