Abstract
BackgroundThe prognosis of human astrocytoma is poor, and the molecular alterations underlying its pathogenesis still needed to be elucidated. Nucleolar and spindle associated protein 1 (NUSAP1) was observed in several types of cancers, but its role in astrocytoma remained unknown.MethodsThe expression of NUSAP1 in astrocytoma cell lines and tissues were measured with western blotting and Real-Time PCR. Two hundred and twenty-one astrocytoma tissue samples were analyzed by immunochemistry to demonstrate the correlation between the NUSAP1 expression and clinicopathological characteristics. 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, colony formation, transwell matrix penetration assay, wound healing assay and anchorage-independent growth assay were used to investigate the biological effect of NUSAP1 in astrocytoma. An intracranial brain xenograft tumor model was used to confirm the oncogenic role of NUSAP1 in human astrocytoma. Luciferase reporter assay was used to investigate the effect of NUSAP1 on Hedgehog signaling pathway.ResultsNUSAP1 was markedly overexpressed in astrocytoma cell lines and tissues compared with normal astrocytes and brain tissues. NUSAP1 was found to be overexpressed in 152 of 221 (68.78%) astrocytoma tissues, and was significantly correlated to poor survival. Further, ectopic expression or knockdown of NUSAP1 significantly promoted or inhibited, respectively, the invasive ability of astrocytoma cells. Moreover, intracranial xenografts of astrocytoma cells engineered to express NUSAP1 were highly invasive compared with the parental cells. With regard to its molecular mechanism, upregulation of NUSAP1 in astrocytoma cells promoted the nuclear translocation of GLI family zinc finger 1 (GLI1) and upregulated the downstream genes of the Hedgehog pathway.ConclusionThese findings indicate that NUSAP1 contributes to the progression of astrocytoma by enhancing tumor cell invasiveness via activation of the Hedgehog signaling pathway, and that NUSAP1 might be a potential prognostic biomarker as well as a target in astrocytoma.
Highlights
The prognosis of human astrocytoma is poor, and the molecular alterations underlying its pathogenesis still needed to be elucidated
Upregulation of Nucleolar and spindle associated protein 1 (NUSAP1) in astrocytoma cell lines and tissues We first analyzed the expression levels of NUSAP1 in astrocytoma, including anaplastic astrocytoma (n = 19) and glioblastoma (n = 81), using data deposited in the Oncomine database
Atlas (TCGA) database revealed that the increase in the mRNA expression of NUSAP1 in astrocytoma tissues was in tandem with the increase in the World Health Organization (WHO) grade of the tumor (Fig. 1b)
Summary
The prognosis of human astrocytoma is poor, and the molecular alterations underlying its pathogenesis still needed to be elucidated. Glioma is the most common primary brain tumor in adults, and it is one of the most fatal human cancers. Despite various improvements in cancer treatment over the last two decades, the outcome of patients with malignant glioma remain very poor [1,2,3]. Astrocytoma, including glioblastoma, which is the most common primary tumor type of human glioma, accounts for 75% of all gliomas [10]. The clinical prognosis of astrocytoma is still mainly dependent on conventional pathological parameters, such as the histological type and tumor grade. Clarifying the molecular mechanisms of astrocytoma and identifying prognostic factors as well as potential targets would have great clinical value
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