Osteopontin regulates human glioma cell invasiveness and tumor growth in mice

Abstract

Human malignant glioma cells are characterized by local invasion. In the present study, we investigated the role of osteopontin (OPN) in the invasiveness of human glioma cells isolated from grade IV tumors. We found that the expression levels of OPN in these cell lines paralleled matrix metalloproteinase-2 (MMP-2) expression and cell invasiveness potential. When U87MG glioma cells (with a high-OPN expression level) were stably transformed with specific small hairpin RNA to knock down OPN expression, MMP-2 secretion, cell invasiveness, and tumor growth in implanted brains were dramatically reduced. Conversely, forced expression of OPN in GBM-SKH glioma cells (which expressed OPN at a low level) increased MMP-2 secretion, enhanced cell invasiveness, and increased tumor growth in a rodent xenograft model. Expression of OPN was associated with increased expression of vimentin and decreased expression of glial fibrillary acidic protein. Treatment of glioma cells with 5-aza-2′-deoxycytidine (5-aza-dC) suppressed OPN expression in a concentration-dependent manner. Suppression of OPN expression by 5-aza-dC was associated with reductions in MMP-2 secretion, vimentin expression, cell invasion, intravasation, and tumor growth. These data suggest that OPN may play important roles in regulating cell invasion in glioma cells and that 5-aza-dC may serve as a therapeutic agent for human gliomas.

Thrombin-cleaved Fragments of Osteopontin Are Overexpressed in Malignant Glial Tumors and Provide a Molecular Niche with Survival Advantage

“…Knockdown of OPN expression in a human GBM cell line by introduction of siRNA led to a reduction in cell proliferation, motility, and migration but no change in tumor-associated angiogenesis. Similar data were obtained by knockdown of OPN expression in human glioma cells (12). However, cleavage of OPN was not assessed in these studies (13).…”

Early Differentiating Mouse Astroglial Progenitors Share Common Protein Signatures with GL261 Glioma Cells

“…Sox2 is identified in several glioma samples [49] and have an important role in the continuous proliferation of glioma cells [50] . Concerning the astrocytic properties of astrocytomas, vimentin is often referred as a marker for these brain tumors [51] , and it was described that its co-expression with nestin may serve as an indicator of an astrocytoma with an enhanced motility and invasive potential [52] . Mature astrocytic markers, such as GFAP, are also described to be expressed in glioma cells [53][54][55] , although Jan et al [51] showed that the malignant progression to a higher degree of invasiveness is associated with an increase in vimentin expression and a progressive loss of GFAP.…”

“…Concerning the astrocytic properties of astrocytomas, vimentin is often referred as a marker for these brain tumors [51] , and it was described that its co-expression with nestin may serve as an indicator of an astrocytoma with an enhanced motility and invasive potential [52] . Mature astrocytic markers, such as GFAP, are also described to be expressed in glioma cells [53][54][55] , although Jan et al [51] showed that the malignant progression to a higher degree of invasiveness is associated with an increase in vimentin expression and a progressive loss of GFAP. Besides the expression of immature and astrocytic cell markers, gliomas also express neuronal proteins such as β-III-tubulin [56,57] and MAP2 [58] , both indicators of a high-grade astrocytoma [58] .…”

Oligodendrogliomlarda osteopontin ekspresyon düzeylerinin histolojik derece ve sağ kalım ile ilişkisi

“…In conclusion, osteopontin expression rates could be associated with histological grades, recurrence and survival of oligodendriomas and could be used as a predictive value. Osteopontin ekstrasellüler matrix ilişkili sialik asitten zengin fosfoglikoprotein yapısında integrin bağlayan bir protein olup kemik resorpsiyonu, yara iyileşmesi, doku yenilenmesi, immunolojik yanıtlar, vaskülarizasyon gibi normal fizyolojik süreçleri düzenler [3,4,5,6]. Aynı zamanda apopitoz, proliferasyon, adezyon, invazyon, metastazda da rol aldığı bilinmektedir.…”

“…Aynı çalışmada glial tümörlerdeki invazyon kapasitesindeki farklılıkların osteopontin düzeyleri ile yakından ilişkili olduğu yönünde görüş belirtilmiştir [3,6,7].…”