Abstract
BackgroundDependence receptors have been proved to act as tumor suppressors in tumorigenesis. Neogenin, a DCC homologue, well known for its fundamental role in axon guidance and cellular differentiation, is also a dependence receptor functioning to control apoptosis. However, loss of neogenin has been reported in several kinds of cancers, but its role in glioma remains to be further investigated.Methodology/Principal FindingsWestern blot analysis showed that neogenin level was lower in glioma tissues than in their matching surrounding non-neoplastic tissues (n = 13, p<0.01). By immunohistochemical analysis of 69 primary and 16 paired initial and recurrent glioma sections, we found that the loss of neogenin did not only correlate negatively with glioma malignancy (n = 69, p<0.01), but also glioma recurrence (n = 16, p<0.05). Kaplan-Meier plot and Cox proportional hazards modelling showed that over-expressive neogenin could prolong the tumor latency (n = 69, p<0.001, 1187.6±162.6 days versus 687.4±254.2 days) and restrain high-grade glioma development (n = 69, p<0.01, HR: 0.264, 95% CI: 0.102 to 0.687). By Methylation specific polymerase chain reaction (MSP), we reported that neogenin promoter was methylated in 31.0% (9/29) gliomas, but absent in 3 kinds of glioma cell lines. Interestingly, the prevalence of methylation in high-grade gliomas was higher than low-grade gliomas and non-neoplastic brain tissues (n = 33, p<0.05) and overall methylation rate increased as glioma malignancy advanced. Furthermore, when cells were over-expressed by neogenin, the apoptotic rate in SHG-44 was increased to 39.7% compared with 8.1% in the blank control (p<0.01) and 9.3% in the negative control (p<0.01).Conclusions/SignificanceThese observations recapitulated the proposed role of neogenin as a tumor suppressor in gliomas and we suggest its down-regulation owing to promoter methylation is a selective advantage for glioma genesis, progression and recurrence. Furthermore, the induction of apoptosis in SHG-44 cells after overexpression of neogenin, indicated that neogenin could be a novel target for glioma therapy.
Highlights
Gliomas are the commonest primary tumors in central nervous system (CNS) arising from neuroepithelial cells and they account for over 50% of primary brain tumors
Surgery is the main therapeutic regimen but microscopic glioblastoma, described as Grade IV glioma, often infiltrates much larger areas than is seen on Magnetic Resonance Imaging (MRI) or Computed Tomography (CT), and as such surgical treatment is at best insufficient, post-operative recurrence is frequently encountered accompanied by short survival time of approximately 14 months [4]
Contrary to the observations made by Meyerhardt and coworkers in 1997 [37], where they reported that neogenin was unaffected in a range of cancers including glioblastoma, the conclusions from Hanninen et al showed that the neogenin mRNA levels were lower in oligodendrogliomas, oligoastrocytomas, medulloblastomas and astrocytomas than in normal brain regions [38]
Summary
Gliomas are the commonest primary tumors in central nervous system (CNS) arising from neuroepithelial cells and they account for over 50% of primary brain tumors. Recent epidemiological reports showed that the incidence of gliomas was about 6.5/ 100,000 and the mortality was about 4.3/100,000 per year and the 5-year survival rate was only 33.4% [1,2]. Depending on pathological characteristics of tumor, gliomas are divided into four grades: I, II, III and IV in ascending order of malignancy. Surgery is the main therapeutic regimen but microscopic glioblastoma, described as Grade IV glioma, often infiltrates much larger areas than is seen on Magnetic Resonance Imaging (MRI) or Computed Tomography (CT), and as such surgical treatment is at best insufficient, post-operative recurrence is frequently encountered accompanied by short survival time of approximately 14 months [4]. There is anticipation that integration of genetic and/or molecular information would assist pathologists in differentiating glioma grades and disease progression rate, and uncover molecular markers that could aid in diagnosis and prognosis. Loss of neogenin has been reported in several kinds of cancers, but its role in glioma remains to be further investigated
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