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

Kafka, Anja and Tomas, Davor and Beroš, Vili and Pećina, Hrvoje Ivan and Zeljko, Martina and Pećina-Šlaus, Nives (2014) Brain metastases from lung cancer show increased expression of DVL1, DVL3 and beta-catenin and down-regulation of E-cadherin. International Journal of Molecular Sciences, 15 (6). pp. 10635-10651. ISSN 1422-0067

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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.

Item Type: Article
Additional Information: © 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (
MeSH: Adaptor Proteins, Signal Transducing/metabolism ; Aged ; Aged, 80 and over ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Brain Neoplasms/secondary ; Cadherins/genetics ; Cadherins/metabolism ; Down-Regulation ; Female ; Humans ; Loss of Heterozygosity ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Phosphoproteins/metabolism ; Wnt Signaling Pathway ; beta Catenin/metabolism
Departments: Hrvatski institut za istraživanje mozga
Katedra za medicinsku biologiju
Depositing User: Marijan Šember
Status: Published
Pećina, Hrvoje IvanUNSPECIFIED
Zeljko, MartinaUNSPECIFIED
Pećina-Šlaus, NivesUNSPECIFIED
Date: 13 June 2014
Date Deposited: 18 Dec 2015 13:40
Last Modified: 17 Jul 2020 08:07
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