SOCS3 promoter methylation is mutually exclusive to EGFR amplification in gliomas and promotes glioma cell invasion through STAT3 and FAK activation

The suppressor of cytokine signaling 3 ( SOCS3 ) gene is one of eight structurally related genes of the SOCS family and has been suggested to function as a tumor suppressor by inhibition of the JAK/STAT signaling pathway. We investigated 60 human gliomas of different histological types for SOCS3 alt...

Full description

Saved in:

Bibliographic Details
Published in:	Acta neuropathologica Vol. 122; no. 2; pp. 241 - 251
Main Authors:	Lindemann, Carina, Hackmann, Oliver, Delic, Sabit, Schmidt, Natalie, Reifenberger, Guido, Riemenschneider, Markus J.
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer-Verlag 01-08-2011 Springer Nature B.V
Subjects:	Blotting, Western Brain cancer Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Cytokines DNA methylation DNA Methylation - genetics DNA Mutational Analysis Enzyme Activation - physiology Focal Adhesion Kinase 1 - metabolism Gene Amplification Genes Genes, erbB-1 Glioma - genetics Glioma - metabolism Glioma - pathology Humans Hypotheses Immunohistochemistry Medicine Medicine & Public Health Neoplasm Invasiveness - genetics Nervous system Neuropathology Neurosciences Original Paper Pathology Promoter Regions, Genetic - genetics Protein expression Reverse Transcriptase Polymerase Chain Reaction Signal transduction Signal Transduction - genetics STAT3 Transcription Factor - metabolism Suppressor of Cytokine Signaling 3 Protein Suppressor of Cytokine Signaling Proteins - genetics Suppressor of Cytokine Signaling Proteins - metabolism Tumors Germany Brain tumor AKT MAPK JAK Astrocytoma Glioblastoma
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	The suppressor of cytokine signaling 3 ( SOCS3 ) gene is one of eight structurally related genes of the SOCS family and has been suggested to function as a tumor suppressor by inhibition of the JAK/STAT signaling pathway. We investigated 60 human gliomas of different histological types for SOCS3 alterations and found frequent SOCS3 promoter hypermethylation and transcriptional downregulation. However, SOCS3 promoter hypermethylation was virtually absent in primary glioblastomas, which are characterized by frequent epidermal growth factor receptor (EGFR) amplification and overexpression. Assessment of the relationship between SOCS3 and EGFR aberrations revealed that SOCS3 promoter hypermethylation was inversely related to both the EGFR gene dosage as well as the EGFR protein expression, thus suggesting SOCS3 inactivation as a mechanism substituting for EGFR activation in a subset of gliomas. In support of this hypothesis, stable shRNA-mediated SOCS3 knock-down in U251 glioblastoma cells resulted in an activation of EGFR-related signaling pathways, i.e. an increase in the activation levels of STAT3, FAK and to a lesser extent MAPK, while the AKT phosphorylation levels remained unaffected. Functionally, SOCS3 -depletion caused strongly increased tumor cell invasion with no obvious effect on tumor cell proliferation. In summary, our findings suggest that SOCS3 inactivation by promoter hypermethylation is mutually exclusive to EGFR activation in gliomas and preferentially promotes glioma cell invasion through STAT3 and FAK activation.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0001-6322 1432-0533
DOI:	10.1007/s00401-011-0832-0