microRNA miR-196a-2 and Breast Cancer: A Genetic and Epigenetic Association Study and Functional Analysis
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- Aaron E. Hoffman
- 1Epidemiology and Public Health and Departments of
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- Tongzhang Zheng
- 1Epidemiology and Public Health and Departments of
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- Chunhui Yi
- 1Epidemiology and Public Health and Departments of
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- Derek Leaderer
- 1Epidemiology and Public Health and Departments of
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- Joanne Weidhaas
- 2Therapeutic Radiology, Yale University School of Medicine;
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- Frank Slack
- 3Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, Connecticut
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- Yawei Zhang
- 1Epidemiology and Public Health and Departments of
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- Trupti Paranjape
- 2Therapeutic Radiology, Yale University School of Medicine;
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- Yong Zhu
- 1Epidemiology and Public Health and Departments of
抄録
<jats:title>Abstract</jats:title> <jats:p>Increasing evidence has suggested that microRNAs (miRNA) play an important role in tumorigenesis. As transcriptional regulators, altered miRNA expression may affect many cancer-related biological pathways, indicating that miRNAs can function as tumor suppressors and/or oncogenes. We first performed a genetic association analysis by screening genetic variants in 15 miRNA genes and detected that a common sequence variant in hsa-miR-196a-2 (rs11614913, C→T) was significantly associated with decreased breast cancer risk (for homozygous variant: odds ratio, 0.44; 95% confidence interval, 0.28-0.70). Hypermethylation of a CpG island upstream (-700 bp) of the miR-196a-2 precursor was also associated with reduced breast cancer risk (odds ratio, 0.35; 95% confidence interval, 0.15-0.81). By delivering expression vectors containing either wild-type or mutant precursors of miR-196a-2 into breast cancer cells, we showed that this variant led to less efficient processing of the miRNA precursor to its mature form as well as diminished capacity to regulate target genes. A whole-genome expression microarray was done and a pathway-based analysis identified a cancer-relevant network formed by genes significantly altered following enforced expression of miR-196a-2. Mutagenesis analysis further showed that cell cycle response to mutagen challenge was significantly enhanced in cells treated with variant miR-196a-2 compared with cells treated with the wild-type. Taken together, our findings suggest that miR-196a-2 might have a potentially oncogenic role in breast tumorigenesis, and the functional genetic variant in its mature region could serve as a novel biomarker for breast cancer susceptibility. [Cancer Res 2009;69(14):5970–7]</jats:p>
収録刊行物
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- Cancer Research
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Cancer Research 69 (14), 5970-5977, 2009-07-15
American Association for Cancer Research (AACR)
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キーワード
詳細情報 詳細情報について
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- CRID
- 1362544419416530560
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- ISSN
- 15387445
- 00085472
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- データソース種別
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- Crossref