engleski

Role of conserved biological pathways and functioning of mismatch repair genes in meningioma progression

Conserved biological pathways such as Wnt signaling pathway and epithelial to mesenchymal transition (EMT) are essential during the embryonic development but can also play a role in tumorigenesis. Resurgence of these pathways with malfunction of p53 tumor suppressor gene and mismatch repair system can give rise to development and progression of tumors. In our research, we studied these cellular events and their functionality in intracranial meningioma – tumors which have three stages of progression, from benign (grade I) to malignant (grade III). By analyzing main effector molecules: p53 (TP53), beta-catenin, E-cadherin (CDH1), MLH1 and MSH2 we can reveal patterns of malignant development and valuable biomarkers of tumor progression. Genetic changes (loss of heterozygosity, microsatellite instability) in TP53, CDH1 and molecules involved in mismatch repair system – MLH1 and MSH2 were analyzed by PCR/RFLP, followed by electrophoresis on Spreadex gels. To assess expression and localization of E-cadherin, beta-catenin and p53, we used DAB-labelled immunohistochemical reaction (EnVisionTM, Dako REALTM) and monoclonal antibody for each protein. Our results showed that levels of the p53 and beta- catenin were significantly negatively correlated (P=0, 002) and that the expression of p53 was significantly (P=0, 021) associated to higher meningioma grades (II and III), indicating that meningiomas with lost p53 upregulate beta-catenin and activate WNT signaling. We also found strong correlation in genetic changes of CDH1 and both MLH1 and MSH2 genes (χ2=0, 007 and χ2=0, 037), suggesting that loss of function in mismatch repair genes stimulate EMT through loss of E-cadherin.

meningioma ; Wnt signaling pathway ; EMT ; TP53

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