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Loss of membranous expression of beta-catenin is associated with tumor progression in cutaneous melanoma and rarely caused by exon 3 mutations.

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Demunter, Anouk Libbrecht, Louis [UCL] Degreef, Hugo De Wolf-Peeters, Chris van den Oord, Joost J

beta-Catenin plays a fundamental role in the regulation of the E-cadherin-catenin cell adhesion complex. It also plays a role in the Wnt signaling pathway by activating T-cell factor- and lymphoid enhancer factor-regulated gene transcription. The level of beta-catenin in cells is tightly controlled in a multiprotein complex, and mutations in the glycogen synthase kinase 3beta (GSK-3beta) phosphorylation sites of the beta-catenin gene (CTNNB1) result in nuclear and/or cytoplasmic accumulation of beta-catenin and constitutive transactivation of T-cell factor and lymphoid enhancer factor target genes, a mechanism occurring in many cancers. Melanoma cell lines may harbor beta-catenin mutations; in vivo, however, cellular accumulation of beta-catenin is rarely caused by CTNNB1 mutations. In our study, 43 primary cutaneous melanoma and 30 metastases were screened for CTNNB1 exon 3 mutations by using a denaturing gradient gel electrophoresis technique and sequencing. beta-Catenin mutations were found in 2 primary melanomas and 1 metastatic melanoma and were not correlated with nuclear accumulation of beta-catenin in these cases. Cellular expression of beta-catenin was evaluated by immunohistochemistry and by reverse polymerase chain reaction (RT-PCR) in 80 and 70 cases, respectively. Immunohistochemistry revealed a significant loss of membranous beta-catenin staining between the primary and metastatic melanomas as well as between radial and vertical growth phase. RT-PCR showed a significant inverse correlation between the amount of RNA and the proportion of cells with membranous expression of beta-catenin (P =.0015); no correlation existed between the amount of RNA and the number of cells with nuclear or cytoplasmic expression of beta-catenin. In conclusion, nuclear expression of beta-catenin is seen in cutaneous melanoma but, in contrast to the case of many other cancers, does not correlate with tumor stage or mutation status. A combination of immunohistochemistry and RT-PCR showed that down-regulation of membranous beta-catenin was associated with an increased amount of beta-catenin RNA in primary or metastatic melanoma. Our results suggest that posttranslational events, rather than CTNNB1 mutations, are responsible for the altered distribution of beta-catenin in cutaneous melanoma.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2002
Language Anglais
Journal information "Modern Pathology" - Vol. 15, no.4, p. 454-461 (2002)
Peer reviewed yes
Publisher Nature Publishing Group ((United Kingdom) London)
issn 0893-3952
e-issn 1530-0285
Publication status Publié
Affiliation [KUL]
MESH Subject Base Sequence ; Immunohistochemistry ; Melanoma ; Mutation ; Skin Neoplasms ; Trans-Activators ; beta Catenin ; Cell Membrane ; Cytoskeletal Proteins ; DNA Mutational Analysis ; DNA, Neoplasm ; Disease Progression ; Exons ; Gene Expression ; Humans
Keywords beta-Catenin ; DGGE ; Immunohistochemistry ; Melanoma ; RT-PCR ; Tumorigenesis
Links
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Bibliographic reference Demunter, Anouk ; Libbrecht, Louis ; Degreef, Hugo ; De Wolf-Peeters, Chris ; van den Oord, Joost J. Loss of membranous expression of beta-catenin is associated with tumor progression in cutaneous melanoma and rarely caused by exon 3 mutations.. In: Modern Pathology, Vol. 15, no.4, p. 454-461 (2002)
Permanent URL http://hdl.handle.net/2078/187230