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Abstract
BackgroundRetinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) displays strong tumor suppressive activities, and its expression is often silenced in many types of human tumors. However, the relationship between RIZ1 expression and glioma prognosis remains unclear.MethodsThe dysregulation of RIZ1 was evaluated using real-time polymerase chain reaction, western blot, and immunohistochemical analysis of gliomas from 51 patients. Correlation analysis was performed to examine relationships between RIZ1 immunoreactivity, clinicopathological features, and patient prognosis. Also, human malignant glioma U87 and U251 cell lines were stably transduced with ectogenic RIZ1 using a lentiviral vector to investigate the effects of induced expression of RIZ1 on cell proliferation, cell cycle, and apoptosis.ResultsReal-time polymerase chain reaction and western blot analysis showed that RIZ1 was downregulated in high-grade gliomas compared with low-grade gliomas and normal brain tissue. Immunohistochemistry showed less RIZ1 labeling in high-grade gliomas than in low-grade gliomas. There was a negative correlation between RIZ1 and Ki-67 immunoreactivity. Clinicopathological evaluation revealed that RIZ1 expression was negatively correlated with tumor grade and patient age. Kaplan-Meier survival analysis showed a positive correlation between RIZ1 immunoreactivity level and progression-free and overall survival times. Multivariate analysis showed that high RIZ1 expression was an independent prognostic factor for patients with gliomas. Induced expression of RIZ1 in U87 and U251 cells reduced cell proliferation and increased apoptosis, and cell cycle analysis revealed that a majority of cells were arrested at G2-M. Moreover, transfection with a RIZ1 expression vector increased p53 and caspase-3 expression and decreased p-IKBα and p-AKT protein levels, suggesting that RIZ1 may stimulate p53-mediated apoptosis and inhibit p-IKBα and p-AKT signaling pathways.ConclusionsOur results suggest that high RIZ1 labeling is indicative of lower grades of gliomas and is associated with better progression-free and overall survival rates. Therefore, RIZ1 may be a promising therapeutic target for patients with gliomas.
Highlights
Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) displays strong tumor suppressive activities, and its expression is often silenced in many types of human tumors
Downregulation of RIZ1 in high grade glioma (HGG) and glioblastoma multiformes (GBMs) cell lines Real-time polymerase chain reaction (RT-PCR) showed greatly reduced RIZ1 expression in HGGs, whereas R1Z1 was readily detectable in Normal brain tissue (NBT) and low-grade gliomas (LGGs) (Fig. 1a)
Western blotting analysis demonstrated undetectable levels of R1Z1 expression in HGGs and a downregulation of RIZ1 protein expression in low grade gliomas (LGG) compared with NBT (Fig. 2a, b)
Summary
Retinoblastoma protein-interacting zinc-finger gene 1 (RIZ1) displays strong tumor suppressive activities, and its expression is often silenced in many types of human tumors. Similar to p53, RIZ1 serves as a cancer suppressor, as its deletion is observed in various types of human cancers including breast cancer, liver cancer, colorectal cancer, neuroblastoma, chronic myelogenous leukemia, and malignant meningioma [5,6,7,8,9]. It remains unclear whether RIZ1 influences the progression of gliomas
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