期刊
CELL CYCLE
卷 14, 期 22, 页码 3644-3655出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1104443
关键词
c-Met; glioblastoma; hepatocyte growth factor; invasion; -catenin
类别
资金
- Instituto de Salud Carlos III
- Fondo Europeo de Desarrollo Regional (FEDER) [PI080790, PI1301980]
- UdL
- Agaur-Generalitat de Catalunya
- Xarxa de Bancs de Tumors de Catalunya (XBTC)
- IRBLleida Biobank [B.0000682]
- Plataforma Biobancos [PT13/0010/0014]
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/-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 -catenin is phosphorylated at Y142 by recombinant c-Met kinase and downstream of HGF signaling in neurons. Here we studied phosphoY142 (PY142) -catenin and dephospho S/T -catenin (a classical Wnt transducer) in glioma biopsies, GBM cell lines and biopsy-derived glioma cell cultures. We found that PY142 -catenin mainly localizes in the nucleus and signals through transcriptional activation in GBM cells. Tissue microarray analysis confirmed strong nuclear PY142 -catenin immunostaining in astrocytoma and GBM biopsies. By contrast, active -catenin showed nuclear localization only in GBM samples. Western blot analysis of tumor biopsies further indicated that PY142 and active -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 -catenin and Snail/Slug. Importantly, the expression of mutant Y142F -catenin decreased cell detachment and invasion induced by HGF in GBM cell lines and biopsy-derived cell cultures. Our results identify PY142 -catenin as a nuclear -catenin signaling form that downregulates adhesion and promotes GBM cell invasion.
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