Upregulated β1-6 branch N-glycan marks early gliomagenesis but exhibited biphasic expression in the progression of astrocytic glioma.

Abstract

Glioma is the world's commonest primary brain malignancy with much of its biology relating to translational and post-translational events still unknown. In this study, we investigated the clinicopathological significance of N-linked β1-6-GlcNAc branches and GnT-V enzyme in the development and progression of astrocytic glioma. Expression of GnT-V and its GlcNAc-β1-6 oligosaccharides by-product together with Con-A binding sugars were assessed immunohistochemically on tissue microarrays of 16 normal brain and 159 tissue samples of astrocytomas of variable grades and histology. Although tissues of both grade I astrocytomas and normal brain showed considerably higher GnT-V expression, GlcNAc-β1-6 expression was significantly high only in tissues of grade I astrocytomas (p < 0.001), which is attributable to elevated levels of the precursor Con-A binding sugar moieties (p < 0.001). The activity of GnT-V enzyme was found to be dependent on the degree of glioma pathogenesis, as the GlcNAc-β1-6 branched expression diminished with every progressive grade of glioma, reaching minimum in glioblastoma (p < 0.001). Having biphasic activity in gliomagenesis, the role of GnT-V in glioma was deciphered by generating different ectopic GnT-V expressions in U-87 cells, which showed the highest GnT-V expression among selected glioma cell lines. Transient GnT-V rescue was achieved in knockdown clones by transfection with GnT-V expression vector. Suppression of GnT-V in U-87 cells slowed cell proliferation with G0/G1 cell cycle phase arrest. Reduced tumorigenicity, invasiveness and cell-ECM interactions were also associated with suppressed in vitro GnT-V activity suggesting GnT-V may act as an oncoprotein. We report for the first time that GnT-V products are involved in early gliomagenesis but their reduced expression, correlating with low Con-A binding sugars level found in high tumor grades predicts the loss of total N-glycosylation in glioma development and may be of potential diagnostic and/or prognostic value in astrocytoma.

• Authors: Arshad Ahmed Padhiar, Jianhui Fan, Ying Tang, Juanhan Yu, Shujing Wang, Linhua Liu, Bachir Niang, Max Efui Annani-Akollor, Lifen Wang, Qi Wang, Jianing Zhang
• Journal: American journal of cancer research (Am J Cancer Res) Vol. 5 Issue 3 Pg. 1101-16 ( 2015) ISSN: 2156-6976 [Print] United States
• PMID: 26045989 (Publication Type: Journal Article)