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

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.

HS2ST1‐dependent signaling pathways determine breast cancer cell viability, matrix interactions, and invasive behavior

“…In this report we demonstrate a novel role for HS2ST1 in modulating breast cancer cell invasiveness via central signaling pathways including MAPK and Wnt (Figure 6F). Our findings are in line with studies in glioma, indicating a downregulation of HS2ST1 and other HS sulfotransferases 50 . Mechanistically, HSPGs modulate MAPK signaling, promoting proliferation, migration, and invasion 45,51‐53 .…”

“…EGFR, known to be overexpressed and activated in approximately 20%‐25% of cancers, 55 acts as a central point for the activation and crosstalk with many signaling pathways relevant to tumor migration and invasion 56 . MAPK and other kinases like phosphatidylinositol‐3‐kinase (PI3‐K) act downstream of EGFR activation, promoting tumor cell migration and invasion 50,57‐59 . In addition, decreased activation or inhibition of p38 MAPK decreases breast cancer metastasis 60 …”

Chemoradiotherapy Increases Intratumor Heterogeneity of HPSE Expression in the Relapsed Glioblastoma Tumors

“…Overexpression of HPSE in U87 glioma cells increases their invasion [17], and in U251n also increased cell invasion, proliferation and anchorage-independent colony formation [20]. We have previously shown that HPSE is down-regulated in gliomas Grade II-IV at the mRNA level, and there is a significant decrease of HPSE protein in tumor and paratumorous glioblastoma tissues compared with the normal tissue [19].…”

“…Previously, a significant decrease of mRNA levels of HPSE in Grade II-IV gliomas and heterogeneous distribution of HPSE protein in primary glioblastomas were demonstrated [19]. To investigate a hypothesis on a potential negative effect of anti-GBM treatment on HPSE and HS content and distribution in GBM tissues, we collected matched pairs of primary and relapsed GBM tumors from the same patient (n = 8).…”

“…Previously, we have shown that mRNA level of HPSE is significantly decreased in Grade II-IV gliomas [19] and distribution of its substrate HS is associated with low relapse-free survival of the glioma patients [4]. To study a possible effect of adjuvant anti-glioblastoma chemoradiotherapy on HPSE expression and its interrelation with HS content, we performed their comparative analysis in primary tumors and the relapsed tumors developed after the treatment.…”