Role of glycosyltransferase PomGnT1 in glioblastoma progression.

Abstract

BACKGROUND:

Glioblastoma multiforme (GBM) is the most aggressive and invasive brain tumor, for which novel prognostic markers and predictors of therapeutic response are urgently needed. We reported previously that levels of peptide-O-linked mannose β-1,2-N-acetylglucosaminyltransferase 1 (PomGnT1) in glioma specimens correlated with tumor grade. However, the prognostic significance of PomGnT1 in glioma patients and its function in GBM progression remain unknown.

METHODS:

Clinical relevance of PomGnT1 in GBM patients' prognosis was analyzed both in a clinically annotated expression dataset of 446 GBM tumor specimens and in 82 GBM tumor samples collected at our institution. The function of PomGnT1 in glioma growth and invasion, and the underlying mechanisms of PomGnT1 regulation were explored in vitro and in vivo.

RESULTS:

PomGnT1 expression in GBM tissues was closely associated with poor prognosis in GBM patients. Forced overexpression of PomGnT1 in glioblastoma cells impaired cell adhesion and increased their proliferation and invasion in vitro. Subsequent in vivo experiments showed that overexpression of PomGnT1 promoted tumor growth and shortened the survival time of tumor-bearing mice in an orthotopic model. Conversely, stable short hairpin RNA-mediated knockdown of PomGnT1 expression produced opposite effects both in vitro and in vivo. Mechanistic studies revealed that activation of epidermal growth factor receptor (EGFR) resulted in EGFR/extracellular signal-regulated kinase-dependent upregulation of PomGnT1, downregulation of receptor-type protein tyrosine phosphatase β, and activation of β-catenin pathway signaling.

CONCLUSION:

These findings suggest that PomGnT1 promotes GBM progression via activation of β-catenin and may serve as a prognostic factor for glioma patient survival as well as a novel molecular target for anticancer therapy in malignant glioma.

• Authors: Jin Lan, Pin Guo, Yingying Lin, Qing Mao, Liemei Guo, Jianwei Ge, Xiaoxiong Li, Jiyao Jiang, Xinjian Lin, Yongming Qiu
• Journal: Neuro-oncology (Neuro Oncol) Vol. 17 Issue 2 Pg. 211-22 (Feb 2015) ISSN: 1523-5866 [Electronic] England
• PMID: 25085363 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• beta Catenin
• N-Acetylglucosaminyltransferases
• protein O-mannose beta-1,2-N-acetylglucosaminyltransferase
• ErbB Receptors
• Receptor-Like Protein Tyrosine Phosphatases, Class 5

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Brain Neoplasms (diagnosis, metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Disease Progression
• ErbB Receptors (metabolism)
• Female
• Glioblastoma (diagnosis, metabolism)
• Humans
• MAP Kinase Signaling System
• Male
• Mice
• Mice, Nude
• Middle Aged
• N-Acetylglucosaminyltransferases (metabolism)
• Neoplasm Invasiveness
• Prognosis
• Receptor-Like Protein Tyrosine Phosphatases, Class 5 (metabolism)
• Survival Rate
• beta Catenin (metabolism)