Versican isoform V1 regulates proliferation and migration in high-grade gliomas

Abstract

Versican is a large chondroitin sulphate proteoglycan produced by several tumor cell types, including high-grade gliomas. Increased expression of distinct versican isoforms in the extracellular matrix plays a role in tumor cell growth, adhesion and migration. We have recently shown that transforming growth factor (TGF-beta)2, an important modulator of glioma invasion, interacts with versican isoforms V0/V1 during malignant progression of glioma in vitro. However, the distinct subtype of versican that modulates these effects could not be specified. Here, we show that transient down-regulation of V1 by siRNA leads to a significant reduction of proliferation and migration in glioblastoma cell lines and glioblastoma progenitor cells, whereas tumor cell attachment stays unaffected. We conclude that V1 plays a predominant role in modulating central pathophysiological mechanisms as proliferation and migration in glioblastoma. Considering that TGF-beta is a master regulator of glioma pathophysiology, and that V0/1 is induced by TGF-beta2, therapeutic regulation of V1 may induce meaningful effects on glioma cell migration not only in vitro, but also in vivo.

Immune microenvironment of gliomas

“…220 This upregulation is mediated by the Toll-like receptor (TLR)2 Immune microenvironment of gliomas A Gieryng et al signaling. 221 TLRs belong to the superfamily of pattern recognition receptors that classically activate and mediate pro-inflammatory responses in innate immune cells by recognizing invading pathogens. TLR2 is highly expressed in all gliomas compared with non-tumor tissue, and patients with high TLR2 expression had reduced survival compared with patients having lower TLR2 expression.…”

“…220 TGF-β2 has been shown to interact with versican V1 and support glioma proliferation and invasion. 221 In the ECM, versican interacts with various partners, such as tenascin-R, fibulin-1, fibrillin-1, fibronectin, P-and L-selectin, and various chemokines via the globular domains or GAG chains. 223 Versican can also bind to the epidermal growth factor receptor, the cell-surface proteins CD44 and integrin β1.…”

Molecular Mechanisms of Glioma Cell Motility

“…A subgroup of CSPG, the lecticans, forms tertiary complexes with hyaluronan and TN-R. Three of them, versican, BEHAB/brevican, and neurocan, are overexpressed in glioma and enhance glioma motility (84)(85)(86).…”

“…NFkB finally upregulates the expression of MMP-9 (152). Other mechanisms of TGF-β influencing the ECM and promoting migration include the upregulation of integrin avβ3 and the versican isoforms V0/V1 (84,153). Furthermore, TGF-β suppresses phosphatase and tensin homolog (PTEN) in glioma cells through enhanced miR10a/b expression (154).…”

Proteoglycans in normal physiology and carcinogenesis

“…Подавление экс-прессии версикана V1 с помощью малых интерфери-рующих РНК приводит к значительному снижению пролиферации и миграции клеток глиомы, что под-держивает предположение о проканцерогенных эффек-тах версикана V1 в регуляции пролиферации и миграции опухолевых клеток при развитии глиобластомы [70].…”