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: | , , , , , , , , , , , , |
| 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 |
| Online Access: | Get full text |
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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 |
| Author_xml | – sequence: 1 givenname: Gabriel surname: Schmid fullname: Schmid, Gabriel organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 2 givenname: Sara surname: Notaro fullname: Notaro, Sara organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck, Department of Gynecology and Obstetrics, University of Brescia – sequence: 3 givenname: Daniel surname: Reimer fullname: Reimer, Daniel organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 4 givenname: Samira surname: Abdel-Azim fullname: Abdel-Azim, Samira organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 5 givenname: Michaela surname: Duggan-Peer fullname: Duggan-Peer, Michaela organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 6 givenname: Jessica surname: Holly fullname: Holly, Jessica organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 7 givenname: Heidi surname: Fiegl fullname: Fiegl, Heidi organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 8 givenname: Julia surname: Rössler fullname: Rössler, Julia organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 9 givenname: Annemarie surname: Wiedemair fullname: Wiedemair, Annemarie organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 10 givenname: Nicole surname: Concin fullname: Concin, Nicole organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 11 givenname: Peter 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 – sequence: 12 givenname: Christian surname: Marth fullname: Marth, Christian organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck – sequence: 13 givenname: Alain Gustave surname: Zeimet fullname: Zeimet, Alain Gustave email: alain.zeimet@uki.at organization: Department of Obstetrics and Gynaecology, Medical University of Innsbruck |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26879132$$D View this record in MEDLINE/PubMed |
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| Keywords | Epigenetics Promotor hypermethylation Gene-silencing miR-34a Ovarian cancer |
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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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| 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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