title: Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion.
abstract: Glioblastoma multiforme (GBM) is a fast growing brain tumor characterized by extensive infiltration into the surrounding tissue and one of the most aggressive cancers. GBM is the most common glioma (originating from glial-derived cells) that either evolves from a low grade astrocytoma or appears de novo. Wnt/β-catenin and Hepatocyte Growth Factor (HGF)/c-Met signaling are hyperactive in human gliomas, where they regulate cell proliferation, migration and stem cell behavior. We previously demonstrated that β-catenin is phosphorylated at Y142 by recombinant c-Met kinase and downstream of HGF signaling in neurons. Here we studied phosphoY142 (PY142) β-catenin and dephospho S/T β-catenin (a classical Wnt transducer) in glioma biopsies, GBM cell lines and biopsy-derived glioma cell cultures. We found that PY142 β-catenin mainly localizes in the nucleus and signals through transcriptional activation in GBM cells. Tissue microarray analysis confirmed strong nuclear PY142 β-catenin immunostaining in astrocytoma and GBM biopsies. By contrast, active β-catenin showed nuclear localization only in GBM samples. Western blot analysis of tumor biopsies further indicated that PY142 and active β-catenin accumulate independently, correlating with the expression of Snail/Slug (an epithelial-mesenchymal transition marker) and Cyclin-D1 (a regulator of cell cycle progression), respectively, in high grade astrocytomas and GBMs. Moreover, GBM cells stimulated with HGF showed increasing levels of PY142 β-catenin and Snail/Slug. Importantly, the expression of mutant Y142F β-catenin decreased cell detachment and invasion induced by HGF in GBM cell lines and biopsy-derived cell cultures. Our results identify PY142 β-catenin as a nuclear β-catenin signaling form that downregulates adhesion and promotes GBM cell invasion.
authors.affiliation: a Departments of Basic Medical Sciences & Experimental Medicine ; University of Lleida & IRBLleida ; Lleida , Spain.
authors.forename: Mireia
authors.initials: M
authors.lastname: Náger
authors.affiliation: b Immunohistochemical and Biostatistics and Epidemiology Units; IRBLleida ; Lleida , Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.affiliation: a Departments of Basic Medical Sciences & Experimental Medicine ; University of Lleida & IRBLleida ; Lleida , Spain.
authors.forename: Deepshikha
authors.initials: D
authors.lastname: Bhardwaj
authors.affiliation: b Immunohistochemical and Biostatistics and Epidemiology Units; IRBLleida ; Lleida , Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Valls
authors.affiliation: c Institute of Neuropathology; Hospital de Bellvitge-IDIBELL ; Barcelona , Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Ferrer
authors.affiliation: d Neurosurgery Unit; Hospital Arnau de Vilanova ; Lleida , Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Nogués
authors.affiliation: a Departments of Basic Medical Sciences & Experimental Medicine ; University of Lleida & IRBLleida ; Lleida , Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Cantí
authors.affiliation: a Departments of Basic Medical Sciences & Experimental Medicine ; University of Lleida & IRBLleida ; Lleida , Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Herreros
mesh_terms: D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism* / Q000648:ultrastructure; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D010766:Phosphorylation; D061251:Primary Cell Culture; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin; D019859:Proto-Oncogene Proteins c-met
keywords: c-Met; glioblastoma; hepatocyte growth factor; invasion; β-catenin