Tumor suppressor gene E-cadherin and its role in normal and malignant cells

E-cadherin tumor suppressor genes are particularly active area of research in development and tumorigenesis. The calcium-dependent interactions among E-cadherin molecules are critical for the formation and maintenance of adherent junctions in areas of epithelial cell-cell contact. Loss of E-cadherin-mediated-adhesion characterises the transition from benign lesions to invasive, metastatic cancer. Nevertheless, there is evidence that E-cadherins may also play a role in the wnt signal transduction pathway, together with other key molecules involved in it, such as beta-catenins and adenomatous poliposis coli gene products. The structure and function of E-cadherin, gene and protein, in normal as well as in tumor cells are reviewed in this paper

Wnt signal transduction pathway and apoptosis: a review

The association between the wnt signaling pathway and apoptosis has become more firmly established in the recent scientific literature. Many reports indicate that the wnt signaling pathway regulates apoptosis through a variety of mechanisms

Molecular Genetics of Intracranial Meningiomas with Emphasis on Canonical Wnt Signalling.

Research over the last decade recognized the importance of novel molecular pathways in pathogenesis of intracranial meningiomas. In this review, we focus on human brain tumours meningiomas and the involvement of Wnt signalling pathway genes and proteins in this common brain tumour, describing their known functional effects. Meningiomas originate from the meningeal layers of the brain and the spinal cord. Most meningiomas have benign clinical behaviour and are classified as grade I by World Health Organization (WHO). However, up to 20% histologically classified as atypical (grade II) or anaplastic (grade III) are associated with higher recurrent rate and have overall less favourable clinical outcome. Recently, there is emerging evidence that multiple signalling pathways including Wnt pathway contribute to the formation and growth of meningiomas. In the review we present the synopsis on meningioma histopathology and genetics and discuss our research regarding Wnt in meningioma. Epithelial-to-mesenchymal transition, a process in which Wnt signalling plays an important role, is shortly discussed

Gubitak heterozigotnosti gena APC u slučaju vestibularnog švanoma procijenjen dvama intragenskim biljezima

Schwannomas are benign encapsulated tumors of Schwann cells, the main peripheral glia cells. The majority of schwannomas arise spontaneously and account for 8% of intracranial tumors. Those involving the cerebellopontine angle are schwannomas in 90% of cases. A case is presented of the loss of heterozygosity of the adenomatous polyposis coli (APC) gene in a female patient with cranial schwannoma from Croatia. The observed change of the APC gene was investigated by use of two intragenetic markers. In the light of novel findings on merlin connection to the wnt signaling reported in the literature, the finding of gross deletion in a patient with cranial vestibular schwannoma is a relevant genetic event.Švanomi (neurinomi, neurilemomi) su dobroćudni tumori podrijetlom od Schwannovih stanica, glavnih perifernih glia stanica. Većina švanoma javlja se spontano, tj. sporadično u populaciji, a pojavnost im iznosi 8% ukupnog broja intrakranijskih tumora. Tumori smješteni u pontocerebelarnom kutu su u 90% slučajeva upravo švanomi. U ovom radu prikazan je nalaz gubitka heterozigotnosti gena APC (adenomatous polyposis coli) u bolesnice sa švanomom iz Hrvatske. Velika delecija gena APC istražena je i dokazana uporabom dvaju intragenskih biljega. U svjetlu novih spoznaja o vezi merlina, produkta gena NF 2, i signalnog puta wnt čiji je APC sudionik, opisani nalaz o gubitku heterozigotnosti predstavlja vrijedan doprinos genetičkom profilu švanoma

Optimal amplification conditions for D16S3399 polymorphic STS axin-1 gene marker

We investigated D16S3399 marker and affirmed it as a highly polymorphic marker useful for the analysis of the human axin-1 gene. Axin-1 acts as a tumor suppressor gene and its protein is an inhibitor of the Wnt signaling pathway. We report on heterozygosity status, alleles frequency observed in a preliminary group of Croatian subjects and the optimal amplification conditions for D16S3399 marker. The amplified CA repeat was confirmed by direct sequencing

Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin

The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p=0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p=0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain

The cellular story of dishevelleds

Dishevelled (DVL) proteins, three of which have been identified in humans, are highly conserved components of canonical and noncanonical Wnt signaling pathways. These multifunctional proteins, originally discovered in the fruit fly, through their different domains mediate complex signal transduction: DIX (dishevelled, axin) and PDZ (postsynaptic density 95, discs large, zonula occludens-1) domains serve for canonical beta-catenin signaling, while PDZ and DEP (dishevelled, Egl-10, pleckstrin) domains serve for non-canonical signaling. In canonical or beta-catenin signaling, DVL forms large molecular supercomplexes at the plasma membrane consisting of Wnt-Fz-LRP5/6-DVLAXIN. This promotes the disassembly of the beta-catenin destruction machinery, beta-catenin accumulation, and consequent activation of Wnt signaling. Therefore, DVLs are considered to be key regulators that rescue cytoplasmic beta-catenin from degradation. The potential medical importance of DVLs is in both human degenerative disease and cancer. The overexpression of DVL has been shown to potentiate the activation of Wnt signaling and it is now apparent that up-regulation of DVLs is involved in several types of cancer

Frequency of loss of heterozygosity of the NF2 gene in schwannomas from Croatian patients

Aim To identify gross deletions in the NF2 gene in a panel of schwannomas from Croatian patients in order to establish their frequencies in Croatian population. Methods Changes of the NF2 gene were tested by polymerase chain reaction/loss of heterozygosity (LOH) using two microsatellite markers, D22S444 and D22S929. Results The analysis with both markers demonstrated that 43.75% of schwannomas exhibited LOH of the NF2 gene. The D22S444 region exhibited 45.5% of LOHs and the D22S929 region exhibited 14.3% of LOHs. Four LOHs were found in Antoni B, 2 in Antoni A, and 1 in Antoni A and B type tumors. Conclusion The frequency of changes observed in Croatian patients is broadly similar to that reported in other populations and thus confirms the existing hypothesis regarding the tumorigenesis of schwannomas and contributes to schwannoma genetic profile helping us to better understand its etiology and treatment