Expression and promotor hypermethylation of miR-34a in the various histological subtypes of ovarian cancer

Background An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional t...

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Published in:BMC cancer Vol. 16; no. 1; p. 102
Main Authors: Schmid, Gabriel, Notaro, Sara, Reimer, Daniel, Abdel-Azim, Samira, Duggan-Peer, Michaela, Holly, Jessica, Fiegl, Heidi, Rössler, Julia, Wiedemair, Annemarie, Concin, Nicole, Altevogt, Peter, Marth, Christian, Zeimet, Alain Gustave
Format: Journal Article
Language:English
Published: London BioMed Central 15.02.2016
BioMed Central Ltd
Springer Nature B.V
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ISSN:1471-2407, 1471-2407
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Abstract Background An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional target of p53 which is frequently mutated in epithelial ovarian carcinomas especially in high grade serous cancer. Moreover, methylation of miR-34a CpG Islands was found to down-regulate miR-34a expression. The aim of this study was to investigate the clinical relevance of mir34a as well as its promoter methylation in a subset of 133 ovarian cancers with a special focus on the p53 mutation status, the dualistic type I and type II ovarian cancer model and the different histotypes. Methods One hundred thirty-three epithelial ovarian cancers and 8 samples of healthy ovarian surface epithelium were retrospectively analysed for miR-34a expression with quantitative real-time reverse transcription PCR (qRT-PCR). Gene-specific DNA methylation was evaluated with MethyLight technique. Results Significantly lower miR-34a expression was found in ovarian cancers than in healthy ovarian epithelium ( p =  0.002). The expression of miR-34a was found lower in type II than in type I cancers ( p =  0.037), in p53 mutated as compared to p53 wild type cancers ( p =  0.003) and in high grade compared to in low grade cancers ( p =  0.028). In multivariate COX regression model low expressing miR-34a cancers exhibited a reduced PFS ( p =  0.039) and OS ( p =  0.018). In serous cancers low miR-34a levels showed a worse OS confirmed also in multivariate analysis ( p =  0.022). miR-34a promoter methylation was found higher in type II cancers than in type I ( p =  0.006). mir34a expression and promoter methylation showed an inverse correlation in cancer samples ( p =  0.05). Conclusion We demonstrated a clinical independent role of miR-34a in epithelial ovarian cancers. Moreover, we corroborated the correlation between miR-34a expression and its promoter methylation in a large set of ovarian cancers. The inverse association between miR-34a expression and grading, p53 mutation status and dualistic tumor type classification, together with its prognostic relevance may underline the tumor-suppressive character of miR-34a in ovarian cancer.
AbstractList An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional target of p53 which is frequently mutated in epithelial ovarian carcinomas especially in high grade serous cancer. Moreover, methylation of miR-34a CpG Islands was found to down-regulate miR-34a expression. The aim of this study was to investigate the clinical relevance of mir34a as well as its promoter methylation in a subset of 133 ovarian cancers with a special focus on the p53 mutation status, the dualistic type I and type II ovarian cancer model and the different histotypes. One hundred thirty-three epithelial ovarian cancers and 8 samples of healthy ovarian surface epithelium were retrospectively analysed for miR-34a expression with quantitative real-time reverse transcription PCR (qRT-PCR). Gene-specific DNA methylation was evaluated with MethyLight technique. Significantly lower miR-34a expression was found in ovarian cancers than in healthy ovarian epithelium (p = 0.002). The expression of miR-34a was found lower in type II than in type I cancers (p = 0.037), in p53 mutated as compared to p53 wild type cancers (p = 0.003) and in high grade compared to in low grade cancers (p = 0.028). In multivariate COX regression model low expressing miR-34a cancers exhibited a reduced PFS (p = 0.039) and OS (p = 0.018). In serous cancers low miR-34a levels showed a worse OS confirmed also in multivariate analysis (p = 0.022). miR-34a promoter methylation was found higher in type II cancers than in type I (p = 0.006). mir34a expression and promoter methylation showed an inverse correlation in cancer samples (p = 0.05). We demonstrated a clinical independent role of miR-34a in epithelial ovarian cancers. Moreover, we corroborated the correlation between miR-34a expression and its promoter methylation in a large set of ovarian cancers. The inverse association between miR-34a expression and grading, p53 mutation status and dualistic tumor type classification, together with its prognostic relevance may underline the tumor-suppressive character of miR-34a in ovarian cancer.
Background An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional target of p53 which is frequently mutated in epithelial ovarian carcinomas especially in high grade serous cancer. Moreover, methylation of miR-34a CpG Islands was found to down-regulate miR-34a expression. The aim of this study was to investigate the clinical relevance of mir34a as well as its promoter methylation in a subset of 133 ovarian cancers with a special focus on the p53 mutation status, the dualistic type I and type II ovarian cancer model and the different histotypes. Methods One hundred thirty-three epithelial ovarian cancers and 8 samples of healthy ovarian surface epithelium were retrospectively analysed for miR-34a expression with quantitative real-time reverse transcription PCR (qRT-PCR). Gene-specific DNA methylation was evaluated with MethyLight technique. Results Significantly lower miR-34a expression was found in ovarian cancers than in healthy ovarian epithelium ( p =  0.002). The expression of miR-34a was found lower in type II than in type I cancers ( p =  0.037), in p53 mutated as compared to p53 wild type cancers ( p =  0.003) and in high grade compared to in low grade cancers ( p =  0.028). In multivariate COX regression model low expressing miR-34a cancers exhibited a reduced PFS ( p =  0.039) and OS ( p =  0.018). In serous cancers low miR-34a levels showed a worse OS confirmed also in multivariate analysis ( p =  0.022). miR-34a promoter methylation was found higher in type II cancers than in type I ( p =  0.006). mir34a expression and promoter methylation showed an inverse correlation in cancer samples ( p =  0.05). Conclusion We demonstrated a clinical independent role of miR-34a in epithelial ovarian cancers. Moreover, we corroborated the correlation between miR-34a expression and its promoter methylation in a large set of ovarian cancers. The inverse association between miR-34a expression and grading, p53 mutation status and dualistic tumor type classification, together with its prognostic relevance may underline the tumor-suppressive character of miR-34a in ovarian cancer.
An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional target of p53 which is frequently mutated in epithelial ovarian carcinomas especially in high grade serous cancer. Moreover, methylation of miR-34a CpG Islands was found to down-regulate miR-34a expression. The aim of this study was to investigate the clinical relevance of mir34a as well as its promoter methylation in a subset of 133 ovarian cancers with a special focus on the p53 mutation status, the dualistic type I and type II ovarian cancer model and the different histotypes.BACKGROUNDAn increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional target of p53 which is frequently mutated in epithelial ovarian carcinomas especially in high grade serous cancer. Moreover, methylation of miR-34a CpG Islands was found to down-regulate miR-34a expression. The aim of this study was to investigate the clinical relevance of mir34a as well as its promoter methylation in a subset of 133 ovarian cancers with a special focus on the p53 mutation status, the dualistic type I and type II ovarian cancer model and the different histotypes.One hundred thirty-three epithelial ovarian cancers and 8 samples of healthy ovarian surface epithelium were retrospectively analysed for miR-34a expression with quantitative real-time reverse transcription PCR (qRT-PCR). Gene-specific DNA methylation was evaluated with MethyLight technique.METHODSOne hundred thirty-three epithelial ovarian cancers and 8 samples of healthy ovarian surface epithelium were retrospectively analysed for miR-34a expression with quantitative real-time reverse transcription PCR (qRT-PCR). Gene-specific DNA methylation was evaluated with MethyLight technique.Significantly lower miR-34a expression was found in ovarian cancers than in healthy ovarian epithelium (p = 0.002). The expression of miR-34a was found lower in type II than in type I cancers (p = 0.037), in p53 mutated as compared to p53 wild type cancers (p = 0.003) and in high grade compared to in low grade cancers (p = 0.028). In multivariate COX regression model low expressing miR-34a cancers exhibited a reduced PFS (p = 0.039) and OS (p = 0.018). In serous cancers low miR-34a levels showed a worse OS confirmed also in multivariate analysis (p = 0.022). miR-34a promoter methylation was found higher in type II cancers than in type I (p = 0.006). mir34a expression and promoter methylation showed an inverse correlation in cancer samples (p = 0.05).RESULTSSignificantly lower miR-34a expression was found in ovarian cancers than in healthy ovarian epithelium (p = 0.002). The expression of miR-34a was found lower in type II than in type I cancers (p = 0.037), in p53 mutated as compared to p53 wild type cancers (p = 0.003) and in high grade compared to in low grade cancers (p = 0.028). In multivariate COX regression model low expressing miR-34a cancers exhibited a reduced PFS (p = 0.039) and OS (p = 0.018). In serous cancers low miR-34a levels showed a worse OS confirmed also in multivariate analysis (p = 0.022). miR-34a promoter methylation was found higher in type II cancers than in type I (p = 0.006). mir34a expression and promoter methylation showed an inverse correlation in cancer samples (p = 0.05).We demonstrated a clinical independent role of miR-34a in epithelial ovarian cancers. Moreover, we corroborated the correlation between miR-34a expression and its promoter methylation in a large set of ovarian cancers. The inverse association between miR-34a expression and grading, p53 mutation status and dualistic tumor type classification, together with its prognostic relevance may underline the tumor-suppressive character of miR-34a in ovarian cancer.CONCLUSIONWe demonstrated a clinical independent role of miR-34a in epithelial ovarian cancers. Moreover, we corroborated the correlation between miR-34a expression and its promoter methylation in a large set of ovarian cancers. The inverse association between miR-34a expression and grading, p53 mutation status and dualistic tumor type classification, together with its prognostic relevance may underline the tumor-suppressive character of miR-34a in ovarian cancer.
ArticleNumber 102
Audience Academic
Author Fiegl, Heidi
Notaro, Sara
Rössler, Julia
Schmid, Gabriel
Altevogt, Peter
Wiedemair, Annemarie
Zeimet, Alain Gustave
Holly, Jessica
Reimer, Daniel
Concin, Nicole
Duggan-Peer, Michaela
Abdel-Azim, Samira
Marth, Christian
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  organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck
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  surname: Abdel-Azim
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  organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck
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  fullname: Rössler, Julia
  organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck
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  fullname: Wiedemair, Annemarie
  organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck
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  surname: Concin
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  organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck
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  surname: Altevogt
  fullname: Altevogt, Peter
  organization: Skin Cancer Unit, German Cancer Research Center (DKFZ), Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg
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  givenname: Christian
  surname: Marth
  fullname: Marth, Christian
  organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck
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  givenname: Alain Gustave
  surname: Zeimet
  fullname: Zeimet, Alain Gustave
  email: alain.zeimet@uki.at
  organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck
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Issue 1
Keywords Epigenetics
Promotor hypermethylation
Gene-silencing
miR-34a
Ovarian cancer
Language English
License Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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Snippet Background An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In...
An increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian...
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StartPage 102
SubjectTerms Aged
Analysis
Biomedical and Life Sciences
Biomedicine
Cancer Research
DNA Methylation - genetics
Female
Gene expression
Gene Expression Regulation, Neoplastic - genetics
Gene Silencing
Health Promotion and Disease Prevention
Humans
Medicine/Public Health
Methylation
MicroRNAs - analysis
MicroRNAs - genetics
MicroRNAs - metabolism
Middle Aged
Oncology
Ovarian cancer
Ovarian Neoplasms - genetics
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - mortality
Ovary - chemistry
Ovary - metabolism
Promoter Regions, Genetic - genetics
Research Article
Risk factors
Surgical Oncology
Survival Analysis
Tissue Array Analysis
Translational oncology
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Title Expression and promotor hypermethylation of miR-34a in the various histological subtypes of ovarian cancer
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