The Role Of Neogenin In Glioma Progression And Its Relative Mechanism

Gliomas are the most common group of primary brain tumor. The main therapyis glioma resection, but they always recur and are ultimately fatal because themechanism is not clear. Loss of function of tumor suppressor genes is one of thehallmarks of tumor genesis and progression. Neogenin, a DCC homologue, wellknown for its fundamental role in axon guidance and cellular differentiation is also adependence receptor controlling apoptosis. Since their discovery, dependencereceptors and their ligands have been implicated in cancers. While neogenin's paucityhas been reported in variety of cancers, its relationship and role in gliomas remain tobe investigated hence this study is in order to explore the correlation between them.Neogenin is high expressed in mouse embryo brain and normal human brain tissuesand locates along the membrane like lines. Western blot analysis showed thatneogenin level was lower in glioma tissues than in their matching surroundingnon-neoplastic tissues(paired t-test, n=13, p<0.01). By using immunohistochemicalanalysis, in primary69patients and16paired initial primary and recurrent gliomatissues we showed that neogenin was down-regulated in gliomas. Statistical analysesshowed that loss of neogenin did not only correlate inversely with glioma malignancy(One-Way ANOVA, n=69, p<0.01), but also accelerated glioma recurrence (pairedt-test, n=16, p<0.05). And it was important that neogenin level in low-grade gliomaswas significantly downregulated when they recurred (paired t-test, n=5, p<0.05). InKaplan-Meier curves and Cox proportional hazards modeling analyses hyperneogeninpatients had a lower high-grade glioma incidence (HR=0.264,95%CI=0.102to0.687, p<0.01). With methylation-specific polymerase chain reaction methylationassay, we reported here that promoter of neogenin was methylated in the31.0%(9/29)of cases gliomas, but methylation was absent from several glioma cell lines.Interesting, the ratio of methylation in high-grade gliomas was different from other tissues (Chi-square test, n=33, p<0.05) and overall methylated frequency wasincreased with glioma malignancy grade upgraded. We proposed that methylationoccurred in the promoter region could be one of the reasons responsible for reductionof neogenin expression in gliomas. Furthermore, neogenin overexpression in SHG-44cells,39.7%cells were transferred to apoptosis compared with8.1%in blank control(p<0.01) and9.3%in negative control (p<0.01). In wound healing model, the index ofcure is18.0%in overexpressive neogenin cells compared to89.7%in empty vectorgroup and93.3%in untreated group (p<0.001). Our results reveals the thedown-regulation of neogenin in gliomas is a selective advantage for gliomatumorigenesis, progression and recurrence, which concurs with the dependencereceptor hypothesis. Thus neogenin acted as a tumor suppressor that regulated gliomadevelopment. Furthermore, overexpression of neogenin induced apoptosis of SHG-44cells and inhibited the migration of glioma cells. This work may offer an originalresearch avenue for glioma therapy by adjustment of neogenin.