Abstract | BACKGROUND: miR-34a functions as an important tumor suppressor during the process of carcinogenesis. However, the mechanism of miR-34a dysregulation in human malignancies has not been well elucidated. Our study aimed to further investigate the regulation mechanism of miR-34a. RESULTS: We found that overexpression of NF-kappa B p65 subunit could increase miR-34a levels in EC109, an esophageal squamous cancer cell line, while ectopic expression of DN IkappaB leaded to a significant reduction of miR-34a expression. Bioinformatics analysis suggested three putative KB sites in promoter region of miR-34a gene. Mutation two of these KB sites impaired p65 induced miR-34a transcriptional activity. Chromatin immunoprecipitation and electrophoretic mobility shift assays both showed that NF-kappaB could specifically bind to the third KB site located in miR-34a promoter. In addition, we found that overexpression of NF-kappaB p65 could not successfully induce miR-34a expression in esophageal cancer cell lines with mutant p53 or decreased p53. Reporter assay further showed that NF-kappaB-induced miR-34a transcriptional activity was reduced by p53 impairment. Nevertheless, CHIP analysis suggested binding of NF-kappaB to miR-34a promoter was not affected in cells with mutant p53. CONCLUSIONS: Our work indicates a novel mechanism of miR-34a regulation that NF-kappaB could elevate miR-34a expression levels through directly binding to its promoter. And wildtype p53 is responsible for NF-kappaB-mediated miR-34a transcriptional activity but not for NF-kappaB binding. These findings might be helpful in understanding miR-34a abnormality in human malignancies and open new perspectives for the roles of miR-34a and NF-kappaB in tumor progression.
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Authors | Juan Li, Kai Wang, Xuedan Chen, Hui Meng, Min Song, Yan Wang, Xueqing Xu, Yun Bai |
Journal | BMC molecular biology
(BMC Mol Biol)
Vol. 13
Pg. 4
(Jan 31 2012)
ISSN: 1471-2199 [Electronic] England |
PMID | 22292433
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- MIRN34 microRNA, human
- MicroRNAs
- NF-kappa B
- Transcription Factor RelA
- Tumor Suppressor Protein p53
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Topics |
- Base Sequence
- Cell Line, Tumor
- Esophageal Neoplasms
(enzymology, genetics)
- Gene Expression Regulation
- Humans
- MicroRNAs
(metabolism)
- Mutation
- NF-kappa B
(genetics, metabolism)
- Promoter Regions, Genetic
- Protein Binding
- Transcription Factor RelA
(genetics, metabolism)
- Transcriptional Activation
- Tumor Suppressor Protein p53
(genetics, metabolism)
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