Clinical StudyDownregulation of chromatin remodeling factor CHD5 is associated with a poor prognosis in human glioma
Introduction
Gliomas are the most common malignancy in the central nervous system for both children and adults. The glioma family includes well-differentiated low grade astrocytomas [World Health Organization (WHO) grade I–II], anaplastic astrocytomas (WHO grade III) and glioblastoma multiforme (GBM, WHO grade IV).1 Despite great progress in therapeutic technologies, including surgery, radiotherapy, photodynamic therapy,2, 3 and chemotherapy, survival remains poor, with less than 3% 5-year survival rate for patients with GBM.4 Recent studies have indicated that age, Karnofsky performance scale (KPS) score, histologic grade, and tumor necrosis are important prognostic factors for gliomas.5 However, the prognosis of both high-and low-grade tumors remains heterogeneous. Curran et al.6 demonstrated that the survival of patients with high-grade gliomas ranges from 5–59 months, and some patients with low-grade tumors have a poorer outcome than expected.
It is widely accepted that both activation of proto-oncogenes and inactivation of tumor suppressor genes are involved in glioma progression. To understand genetic and molecular pathogenic changes during the development of gliomas, it is therefore important to identify novel diagnostic and prognostic markers.
The chromodomain helicase DNA-binding domain (CHD) protein family includes nine members (CHD 1–9), which all contain two N-terminal chromodomains, a helicase-like ATPase motif associated with nucleosome remodeling, and a less well-defined C-terminal DNA binding domain.7 As a member of the CHD family, CHD5 was identified in 2002 as a tumor suppressor gene located at 1p36 in the p19/p53 pathway.8 CHD5 is an unusual CHD member because its expression is found to be limited to the developing brain, adult brain, and adrenal gland, suggesting a role in the development or function of the neural system.9 Its role in tumorigenesis was originally demonstrated by genetic mapping studies in neuroblastomas. In 2003, Thompson et al.10 found that CHD5 maps within a small region of deletion on 1p36.3 in human neuroblastomas; they also detected low or undetectable CHD5 expression in both neuroblastoma cell lines and tissues. Subsequent cumulative research evidence supports CHD5 as a candidate tumor suppressor gene in more than half of human cancers. For example, Wang et al.11 reported that the ectopic expression of CHD5 in laryngeal cancer cells led to significant inhibition of growth and invasiveness; Zhao et al.12 detected low or absent CHD5 expression in lung cancer cell lines and tissues; in epithelial ovarian cancer, Wong et al.13 found that downregulation of CHD5 was an independent adverse prognostic factor for this tumor. These findings suggest that CHD5 deficiency is a common molecular event in human tumorigenesis.
The CHD5 gene was also found to be significantly deleted in glioma cell lines14, 15; however, its expression pattern and clinical significance in human malignant glioma remains unclear. To address this question, CHD5 expression in human gliomas and non-neoplastic brain tissues was measured by real-time quantitative polymerase chain reaction (RT–PCR) assay, Western blot, and immunohistochemistry. The association of CHD5 immunostaining with clinicopathological factors and prognosis in glioma patients was statistically analyzed.
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Patients and tissue samples
This study was approved by the Research Ethics Committee of Tangdu Hospital, Fourth Military Medical University, China. Written informed consent was obtained from all patients. All specimens were handled and anonymized according to ethical and legal standards.
A total of 128 formalin-fixed, paraffin-embedded specimens of gliomas resected between 2000 and 2010 were retrieved from the archives of the Pathology Department of Tangdu Hospital, Fourth Military Medical University, China. All slides
CHD5 mRNA and protein expression in human glioma tissues
CHD5 mRNA expression was detected in 20 glioma and 10 non-neoplastic brain tissues normalized to GAPDH. As shown in Fig. 1A and C, we found that expression of the CHD5 gene was distinctly decreased in glioma tissues compared to non-neoplastic brain tissues, and corresponded to glioma WHO grade; expression in high-grade (III–IV, 0.2 ± 0.01) and low-grade (I–II, 0.9 ± 0.04) gliomas were both significantly lower than expression in non-neoplastic brain tissues (1.8 ± 0.06; p < 0.001 and p < 0.008,
Discussion
Human gliomas are aggressive tumors with a poor prognosis because of their heterogeneous biology, high invasiveness, rapid tumor cell proliferation, and often advanced stage at diagnosis, despite recent advances in diagnostic modalities. Several genetic and molecular mechanisms of tumorigenesis in gliomas have been described; however, many factors affecting tumor progression remain unclear. It is therefore necessary to identify molecular markers related to prognosis that could be used as
Conflicts of interest/Disclosures
The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
Acknowledgements
This work was funded by National Natural Science Foundation of China (NO. 81101736, NO.81272419), Talents Supported Plan Foundation of Tangdu Hospital for Yanyang Tu (2011) and Science and Technology Innovation Foundation of Tangdu Hospital for Yanyang Tu(2012).
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These authors contributed equally to this study.