Header

UZH-Logo

Maintenance Infos

Involvement of PTEN Promoter Methylation in Cerebral Cavernous Malformations


Zhu, Y; Wloch, A; Wu, Q; Peters, C; Pagenstecher, A; Bertalanffy, H; Sure, U (2009). Involvement of PTEN Promoter Methylation in Cerebral Cavernous Malformations. Stroke, 40(3):820-826.

Abstract

BACKGROUND AND PURPOSE: Cerebral cavernous malformations (CCMs) are prevalent cerebral vascular lesions involving aberrant angiogenesis. However, the underlying mechanism is poorly understood. Phosphatase and tension homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is frequently deficient in various pathologies due to mutation or epigenetic alterations. PTEN promoter hypermethylation is a major epigenetic silencing mechanism leading to activation of angiogenesis in tumors. The present study aimed to investigate whether PTEN promoter methylation was involved in CCMs. METHODS: PTEN promoter methylation was detected in surgical specimens of CCMs (n=69) by methylation-specific polymerase chain reaction. The methylation status was correlated to the clinical manifestations and to PTEN expression, which was analyzed by both Western blot and immunohistochemistry. To investigate the endothelial proliferation and the potential signaling pathways affected by PTEN methylation, proliferating cell nuclear antigen as well as phosphor-Akt and phosphor-Erk1,2 were detected by immunofluorescence and Western blot, respectively, in CCM specimens. RESULTS: Methylation-specific polymerase chain reaction revealed PTEN promoter methylation in 15.9% CCMs. Strikingly, 5 of 6 familial CCMs showed PTEN promoter methylation (83.3%), which was significantly higher than in sporadic cases (9.4%; P<0.001). In addition, PTEN promoter methylation appeared more frequently in multiple CCMs, including familial cases (46.7%), than that in single-lesioned CCMs (11.8%; P<0.05). Immunostaining and Western blot revealed a more significant PTEN downregulation in PTEN-methylated CCMs in comparison to PTEN-unmethylated CCMs. Reduced PTEN expression was inversely correlated to the expression of proliferating cell nuclear antigen and to the activation of Erk1,2, but not of Akt. CONCLUSIONS: We reported here for the first time the involvement of PTEN promoter methylation in CCMs, particularly in familial CCMs, suggesting this epigenetic alteration as a potential pathomechanism of CCMs. The identification of Erk1,2 as triggered signaling in the lesions may be valuable for the development of effective therapy for this disease.

Abstract

BACKGROUND AND PURPOSE: Cerebral cavernous malformations (CCMs) are prevalent cerebral vascular lesions involving aberrant angiogenesis. However, the underlying mechanism is poorly understood. Phosphatase and tension homolog deleted on chromosome 10 (PTEN), a tumor suppressor, is frequently deficient in various pathologies due to mutation or epigenetic alterations. PTEN promoter hypermethylation is a major epigenetic silencing mechanism leading to activation of angiogenesis in tumors. The present study aimed to investigate whether PTEN promoter methylation was involved in CCMs. METHODS: PTEN promoter methylation was detected in surgical specimens of CCMs (n=69) by methylation-specific polymerase chain reaction. The methylation status was correlated to the clinical manifestations and to PTEN expression, which was analyzed by both Western blot and immunohistochemistry. To investigate the endothelial proliferation and the potential signaling pathways affected by PTEN methylation, proliferating cell nuclear antigen as well as phosphor-Akt and phosphor-Erk1,2 were detected by immunofluorescence and Western blot, respectively, in CCM specimens. RESULTS: Methylation-specific polymerase chain reaction revealed PTEN promoter methylation in 15.9% CCMs. Strikingly, 5 of 6 familial CCMs showed PTEN promoter methylation (83.3%), which was significantly higher than in sporadic cases (9.4%; P<0.001). In addition, PTEN promoter methylation appeared more frequently in multiple CCMs, including familial cases (46.7%), than that in single-lesioned CCMs (11.8%; P<0.05). Immunostaining and Western blot revealed a more significant PTEN downregulation in PTEN-methylated CCMs in comparison to PTEN-unmethylated CCMs. Reduced PTEN expression was inversely correlated to the expression of proliferating cell nuclear antigen and to the activation of Erk1,2, but not of Akt. CONCLUSIONS: We reported here for the first time the involvement of PTEN promoter methylation in CCMs, particularly in familial CCMs, suggesting this epigenetic alteration as a potential pathomechanism of CCMs. The identification of Erk1,2 as triggered signaling in the lesions may be valuable for the development of effective therapy for this disease.

Statistics

Citations

18 citations in Web of Science®
19 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

0 downloads since deposited on 16 Feb 2009
0 downloads since 12 months

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurosurgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:31 March 2009
Deposited On:16 Feb 2009 14:58
Last Modified:21 Nov 2017 13:58
Publisher:Lippincott Wiliams & Wilkins
ISSN:0039-2499
Additional Information:This is an un-copyedited author manuscript that was accepted for publication in (insert journal name), copyright The American Heart Association. This may not be duplicated or reproduced, other than for personal use or within the “Fair Use of Copyrighted Materials” (section 107, title 17, U.S. Code) without prior permission of the copyright owner, The American Heart Association. The final copyedited article, which is the version of record, can be found at (insert journal URL). The American Heart Association disclaims any responsibility or liability for errors or omissions in this version of the manuscript or in any version derived from it by the National Institutes of Health or other parties.
Publisher DOI:https://doi.org/10.1161/STROKEAHA.108.526376
Official URL:http://stroke.ahajournals.org/cgi/reprint/STROKEAHA.108.526376v1.pdf
PubMed ID:19118244

Download