engleski

Wnt signalling is targeted in meningioma

Meningiomas which originate from the arachnoidal cap cells of the leptomeninges account for approximately 30% of primary intracranial and intraspinal neoplasms. The molecular mechanisms, signaling pathways and candidate genes involved in their development still need elucidation. In the present study we investigated the involvement of Wnt signaling pathway in meningioma by analyzing its key molecules, beta-catenin, APC, DVL3, AXIN1 and E-cadherin. The chosen pathway is well known for its role in development and tumorigenesis. Genetic changes of tumor suppressor genes APC, E-cadherin (CDH1) and AXIN1 were analyzed by PCR/loss of heterozygosity (LOH). Multiplex PCR was used for DVL3 analysis. The expression and cellular localizations of proteins were investigated by immunohistochemistry. The results obtained on APC showed 47% of meningiomas with LOH of this gene. Immunostaining showed that samples with LOHs were accompanied with the absence of APC protein expression or presence of mutant APC proteins (Chi square =13.81, df = 2, P<0.001). Immunostaining showed that beta-catenin was upregulated and transferred to the nucleus in 71, 2% of meningiomas. This high frequency is indicative of oncogenic activation of Wnt signaling. We also showed that nuclear localization of beta-catenin correlates to gross deletions of APC gene (Chi square =21, 96, df = 2, P<0.0001). Downregulation or loss of E- cadherin expression was observed in 58% of samples and gross deletions (LOH) of this gene were found in 32% of meningiomas. Our findings demonstrated that there was significant association between the genetic changes of CDH1 and the nuclear localization of beta-catenin protein (Chi square =5, 25, df =1, P<0, 022). Loss of E-cadherin and beta- catenin’s translocation to the nucleus are two prominent features of epithelial to mesenchymal transition, a process involved in invasion and metastasis of tumors. LOH of AXIN1 gene was observed in 21.1% of meningiomas and AXIN1 expression levels were negative or very weak in 21.9% of meningiomas. All the other samples had AXIN1 localized in both the cytoplasm and nucleus with moderate expression in 34.4% and strong in 43.8%. DVL3 was amplified in 23, 81% of analyzed samples. Microsatellite instability (MSI), the result of impaired cellular mismatch repair, was also detected, MSI for CDH1 gene in 11%, for DVL3 in 9, 52% and for AXIN1 in 5.3% of investigated meningiomas. Our results suggest that Wnt signaling pathway plays important role in meningioma. The ongoing research is aiming to offer new molecular markers for meningioma based on the genetic pathways and molecules involved and help to develop new treatment modalities.

Wnt signalling ; meningioma

nije evidentirano