Abstract
In the search for molecular candidates for targeted meningioma therapies, increasing attention has been paid to the role of signaling pathways in the development and progression of intracranial meningiomas. Although it is well known that the Wnt signaling pathway is involved in meningioma progression, the role of its central mediator, DVL1, is still unclear. In order to investigate the influence of DVL1 gene alterations on the progression of human intracranial meningioma, we focused on its central PDZ domain, which is responsible for DVL interaction with the Fzd receptor and the phosphorylation of DVL mediated through the casein kinases CK1 and CK2. A genetic analysis of genomic instability revealed the existence of microsatellite instability in 9.09% and the loss of heterozygosity in 6.06% of the samples. The sequencing of the PDZ gene region showed repetitive deletions of two bases located in intron 7 and exon 8, and a duplication in intron 8 in most samples, with different outcomes on the biological function of the DVL1 protein. Immunohistochemistry revealed that the nuclear expression of DVL1 was significantly correlated with a higher expression of active β-catenin (p = 0.029) and a higher meningioma grade (p = 0.030), which leads to the conclusion that it could be used as biomarker for meningioma progression and the activation of the Wnt signaling pathway.
Highlights
Intracranial meningioma, with their mostly benign nature and slow growth, can still progress and show malignant characteristics that can lead to poor outcome for patients
Genetic Instability of the DVL1 Gene Recorded with the D1S468 Marker
When considering loss of heterozygosity (LOH), similar findings were described by Nagahata et al [24], who studied DVL1 in breast cancer and found that 10% of the samples harbored LOH of the DVL1 gene, suggesting that DVL1 has a role in breast cancer progression
Summary
Intracranial meningioma, with their mostly benign nature and slow growth, can still progress and show malignant characteristics that can lead to poor outcome for patients. It has been shown that the activation of Wnt signaling can induce the malignant transformation of neural stem cells and contribute to the development of primary brain tumors [11,12,13,14,15,16]. Activation occurs when Wnt ligands bind to membrane receptors called Frizzled. This binding is followed by the activation of a specific member of the Disheveled (Dvl) protein family, which is pulled to the membrane where it promotes the phosphorylation and disassembly of the destruction complex, which targets β-catenin. It has been shown that DVL has nuclear activity by binding to the TCF factor together with the β-catenin and by activating the transcription of Wnt target genes [23]
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