Dataset Information

Wnt/?-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells.

ABSTRACT:

Background

Glioblastoma (GBM) is the most lethal and common type of primary brain tumor. Recent evidence suggests that a subpopulation of GBM cells (glioblastoma stem cells [GSCs]) is critical for tumor progression, invasion, and therapeutic resistance. We and others have demonstrated that MET, a receptor tyrosine kinase, positively regulates the stemness phenotype and radioresistance of GSCs. Here, we interrogated the downstream effector pathways of MET signaling in GSCs.

Methods

We have established a series of GSCs and xenograft tumors derived from freshly dissociated specimens from patients with GBM and characterized a subpopulation enriched with MET activation (MET(high/+)). Through global expression profiling and subsequent pathways analysis, we identified signaling pathways that are enriched in MET(high/+) populations, one of which is Wnt/?-catenin signaling pathway. To determine molecular interaction and the biological consequences of MET and Wnt/?-catenin signaling, we used pharmacological and shRNA-mediated genetic inhibition and performed various molecular and cellular analyses, including flow cytometry, immunohistochemistry, and clonogenicity assays.

Results

We found that Wnt/?-catenin signaling is highly active in MET(high/+) cells, compared with bulk tumor cells. We also showed that Wnt/?-catenin signaling activities in GBM are directly modulated by the addition of ligand-mediated MET activation or MET inhibition. Furthermore, the ectopic expression of active-?-catenin (S37A and S45Y) rescued the phenotypic effects caused by MET inhibition.

Conclusion

These data suggest that Wnt/?-catenin signaling is a key downstream effector of MET signaling and contributes to the maintenance of GSC and GBM malignancy.

SUBMITTER: Kim KH

PROVIDER: S-EPMC3548587 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Wnt/β-catenin signaling is a key downstream mediator of MET signaling in glioblastoma stem cells.

Kim Kang Ho KH Seol Ho Jun HJ Kim Eun Hee EH Rheey Jinguen J Jin Hyun Jin HJ Lee Yeri Y Joo Kyeung Min KM Lee Jeongwu J Nam Do-Hyun DH

Neuro-oncology 20121220 2

<h4>Background</h4>Glioblastoma (GBM) is the most lethal and common type of primary brain tumor. Recent evidence suggests that a subpopulation of GBM cells (glioblastoma stem cells [GSCs]) is critical for tumor progression, invasion, and therapeutic resistance. We and others have demonstrated that MET, a receptor tyrosine kinase, positively regulates the stemness phenotype and radioresistance of GSCs. Here, we interrogated the downstream effector pathways of MET signaling in GSCs.<h4>Methods</h4 ...[more]

PMID: 23258844

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