Abstract
The Y-box binding protein 1 (YB-1) is upregulated in many human malignancies including glioblastoma (GBM). It is also essential for normal brain development, suggesting that YB-1 is part of a neural stem cell (NSC) network. Here, we show that YB-1 was highly expressed in the subventricular zone (SVZ) of mouse fetal brain tissues but not in terminally differentiated primary astrocytes. Conversely, YB-1 knockout mice had reduced Sox-2, nestin, and musashi-1 expression in the SVZ. Although primary murine neurospheres were rich in YB-1, its expression was lost during glial differentiation. Glial tumors often express NSC markers and tend to loose the cellular control that governs differentiation; therefore, we addressed whether YB-1 served a similar role in cancer cells. YB-1, Sox-2, musashi-1, Bmi-1, and nestin are coordinately expressed in SF188 cells and 9/9 GBM patient-derived primary brain tumor-initiating cells (BTIC). Silencing YB-1 with siRNA attenuated the expression of these NSC markers, reduced neurosphere growth, and triggered differentiation via coordinate loss of GSK3-β. Furthermore, differentiation of BTIC with 1% serum or bone morphogenetic protein-4 suppressed YB-1 protein expression. Likewise, YB-1 expression was lost during differentiation of normal human NSCs. Consistent with these observations, YB-1 expression increased with tumor grade (n = 49 cases). YB-1 was also coexpressed with Bmi-1 (Spearmans 0.80, P > 0.001) and Sox-2 (Spearmans 0.66, P > 0.001) based on the analysis of 282 cases of high-grade gliomas. These proteins were highly expressed in 10/15 (67%) of GBM patients that subsequently relapsed. In conclusion, YB-1 correlatively expresses with NSC markers where it functions to promote cell growth and inhibit differentiation.
Highlights
Glioblastoma (GBM), the most common primary brain tumor in adults, is usually associated with a 2-year survival rate of only 10% to 25% [1]
Y-box binding protein 1 (YB-1) is important for the maintenance of mouse neural stem cell (NSC) YB-1 was highly expressed in the subventricular zone (SVZ)
We confirmed the expression of YB-1 in the SVZ of E14 mouse tissues by staining serial sagittal sections for glial fibrillary acidic protein (GFAP) (Fig. 1B) and nestin (Supplementary Fig. S1A), which reportedly mark NSCs [36]
Summary
Glioblastoma (GBM), the most common primary brain tumor in adults, is usually associated with a 2-year survival rate of only 10% to 25% [1]. An intriguing feature of BTICs is that they maintain tumor cells in an undifferentiated state [19] For this reason, new therapeutic approaches that force BTICs to undergo differentiation and/or to cease proliferation are being sought to improve cancer treatment. This was originally discovered through genomewide promoter occupancy studies where YB-1 binds to several genes associated with tumor-initiating cells such as CD44 and CD49f [20, 21] It was expressed in primary mammary progenitor cells from women who had undergone reduction mammoplasties suggesting that it played a role in normal mammary stem cells [20]. We questioned what role YB-1 may play in NSCs and/or BTICs derived from primary brain tumors
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