Hypermethylation and Down-regulation of Neogenin in Gliomas.Identification of Neogenin As Possible Tumour Suppressor in Gliomas

【摘要】：Repressed expression of tumour suppressor genes with concomitant amplification of oncogenes has been a molecular signature in tumorigenesis and cancer progression. The trans-membrane receptor protein, Neogenin, closely related to DCC (deleted in colorectal cancer), structurally and functionally, is renowned for guiding axons during migration, regulating cell differentiation in CNS and beyond and controlling cell division. Emerging data have categorized neogenin in a group of structurally disparate but functionally related, dependence receptor. Dependence receptors have been known to steer cells into apoptosis in environments of ligand unavailability. Since their discovery, dependence receptors and their ligands have been implicated in cancer. The loss of neogenin has been reported in diverse cancers but its correlation with and function in gliomas remains to be further examined hence this work. By using immunohistochemical analysis, Western blot, Methylation specific PCR and Flow-cytometric assay in69glioma tissues, first show that neogenin is down-regulated in gliomas. Secondly, the expression is inversely related to glioma grade. Thirdly, loss of neogenin accompanies glioma recurrence. Fourthly, the hyper-methylation state of neogenin promoter could be responsible for repressed expression suggesting a possible tumour suppressor role of neogenin in gliomas and finally, over-expression of neogenin in SHG44cells, glioma cell line, induces cell death by apoptosis, further supporting its candidacy. These observations confirm the tumour suppressor role of neogenin and postulate it's a selective advantage for tumour progression which concurs with dependence receptor hypothesis. Thus neogenin acts as tumour suppressor that regulates gliomatogenesis and progression. These observations may be relevant towards understanding molecular alterations in gliomas which may aid in designation of gene therapy against cancer, neogenin, as a molecular marker and target for drug development.