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. 2017 Nov 1;18(11):2301.
doi: 10.3390/ijms18112301.

Heparan Sulfate Biosynthetic System Is Inhibited in Human Glioma Due to EXT1/2 and HS6ST1/2 Down-Regulation

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Free PMC article

Heparan Sulfate Biosynthetic System Is Inhibited in Human Glioma Due to EXT1/2 and HS6ST1/2 Down-Regulation

Victor S Ushakov et al. Int J Mol Sci. .
Free PMC article

Abstract

Heparan sulfate (HS) is an important component of the extracellular matrix and cell surface, which plays a key role in cell-cell and cell-matrix interactions. Functional activity of HS directly depends on its structure, which determined by a complex system of HS biosynthetic enzymes. During malignant transformation, the system can undergo significant changes, but for glioma, HS biosynthesis has not been studied in detail. In this study, we performed a comparative analysis of the HS biosynthetic system in human gliomas of different grades. RT-PCR analysis showed that the overall transcriptional activity of the main HS biosynthesis-involved genes (EXT1, EXT2, NDST1, NDST2, GLCE, HS2ST1, HS3ST1, HS3ST2, HS6ST1, HS6ST2, SULF1, SULF2, HPSE) was decreased by 1.5-2-fold in Grade II-III glioma (p < 0.01) and by 3-fold in Grade IV glioma (glioblastoma multiforme, GBM) (p < 0.05), as compared with the para-tumourous tissue. The inhibition was mainly due to the elongation (a decrease in EXT1/2 expression by 3-4-fold) and 6-O-sulfation steps (a decrease in 6OST1/2 expression by 2-5-fold) of the HS biosynthesis. Heparanase (HPSE) expression was identified in 50% of GBM tumours by immunostaining, and was characterised by a high intratumoural heterogeneity of the presence of the HPSE protein. The detected disorganisation of the HS biosynthetic system in gliomas might be a potential molecular mechanism for the changes of HS structure and content in tumour microenvironments, contributing to the invasion of glioma cells and the development of the disease.

Keywords: biosynthesis; extracellular matrix; glioma; heparan sulfate; heparanase; invasion; sulfotransferase; tumour microenvironment.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Transcriptional activity of the HS biosynthetic system in gliomas of different grades. The intensity of the amplified DNA fragments of HS biosynthesis-related genes was normalised to that of GAPDH. The stacked columns reflect the contribution of each gene to the total expression level. Control—para-tumourous brain tissuefrom the Grade II glioma patients. The stacked columns are based on the mean expression levels from triplicate experiments (Origin 8.5; OriginLab Corporation, Northampton, USA); * p < 0.01; ** p < 0.05.
Figure 2
Figure 2
Expression of HS biosynthesis-related genes in human gliomas of different grades. The intensity of the amplified DNA fragments was normalised to that of GAPDH. The graphs show the mean expression levels from triplicate experiments ± SD (Origin 8.5; OriginLab Corporation, Northampton, USA); * p < 0.01.
Figure 3
Figure 3
HPSE expression in the human brain tumours. (A) HPSE mRNA expression levels in tumour samples (real-time RT-PCR). The intensity of the amplified DNA fragments was normalised to that of GAPDH. Bars represent the mean from triplicate experiments ± SD (Origin 8.5; OriginLab Corporation, Northampton, USA); * p < 0.01; (B) Expression and distribution of HPSE protein molecule in glioblastoma tissues. Immunostaining of GBM tumours using anti-HPSE antibodies; counterstaining with Hematoxylin; 1–6 patients; magnification ×400.
Figure 4
Figure 4
Intratumour heterogeneity of HPSE expression in glioblastoma. (A) Immunostaining of GBM tumours using anti-HPSE antibodies. Patients 7 and 8; Fields 1,2,3-observation fields of the histological preparation; counterstaining with Hematoxylin; magnification ×400; (B) Semi-quantitative analysis of anti-HPSE staining intensities in different observation fields. Bars represent the mean from triplicate experiments ± SD (Origin 8.5; OriginLab Corporation, Northampton, USA); 7, 8-patients.

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