Down-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.

<h4>Background</h4>Dependence 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, lo...

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Autores principales:	Xinmin Wu, Yunqian Li, Xilin Wan, Tabitha Mlowoka Kayira, Rangjuan Cao, Xingda Ju, Xiaojuan Zhu, Gang Zhao
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5c7692f269354978a99bee31edab2ebc
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spelling	oai:doaj.org-article:5c7692f269354978a99bee31edab2ebc2021-11-18T07:17:04ZDown-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.1932-620310.1371/journal.pone.0038074https://doaj.org/article/5c7692f269354978a99bee31edab2ebc2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22666451/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Dependence 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.<h4>Methodology/principal findings</h4>Western 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).<h4>Conclusions/significance</h4>These 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.Xinmin WuYunqian LiXilin WanTabitha Mlowoka KayiraRangjuan CaoXingda JuXiaojuan ZhuGang ZhaoPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e38074 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xinmin Wu Yunqian Li Xilin Wan Tabitha Mlowoka Kayira Rangjuan Cao Xingda Ju Xiaojuan Zhu Gang Zhao Down-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.
description	<h4>Background</h4>Dependence 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.<h4>Methodology/principal findings</h4>Western 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).<h4>Conclusions/significance</h4>These 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.
format	article
author	Xinmin Wu Yunqian Li Xilin Wan Tabitha Mlowoka Kayira Rangjuan Cao Xingda Ju Xiaojuan Zhu Gang Zhao
author_facet	Xinmin Wu Yunqian Li Xilin Wan Tabitha Mlowoka Kayira Rangjuan Cao Xingda Ju Xiaojuan Zhu Gang Zhao
author_sort	Xinmin Wu
title	Down-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.
title_short	Down-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.
title_full	Down-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.
title_fullStr	Down-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.
title_full_unstemmed	Down-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.
title_sort	down-regulation of neogenin accelerated glioma progression through promoter methylation and its overexpression in shg-44 induced apoptosis.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/5c7692f269354978a99bee31edab2ebc
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Down-regulation of neogenin accelerated glioma progression through promoter Methylation and its overexpression in SHG-44 Induced Apoptosis.

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