期刊
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
卷 50, 期 10, 页码 4542-4551出版社
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.09-3520
关键词
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资金
- National Eye Institute [RO1 EY13812, EY02162]
- That Man May See Foundation
- Wayne and Gladys Valley Foundation
- Research to Prevent Blindness
- Fight for Sight
PURPOSE. The role of miR-34a, a p53-regulated microRNA, in retinoblastoma (RB) was investigated. METHODS. The expression of miR-34 family members in RB cells was determined by semiquantitative RT-PCR and real-time qPCR. Regulation of miR-34a expression by p53-activating compounds was determined by qPCR analysis. The tumor suppressor functions of miR-34a in RB cell lines were determined by tetrazolium-based cell growth assay and by caspase-3/7 and activated caspase-3 apoptotic activity assays. Additive growth inhibitory properties of miR-34a in combination with topotecan were determined by cell growth assay. miR-34a targets in RB cells were identified by real-time qPCR expression analysis of previously reported and GenMiR++-predicted mRNAs. RESULTS. Differential miR-34a and miR-34b expression was observed in RB cell lines and tumor samples. miR-34a expression could be increased in Y79 cells, but not Weri-Rb1 cells, after p53 activation. This differential regulation was not caused by genomic alterations at the miR-34a p53 binding site or mature gene. Exogenous miR-34a inhibited Y79 and Weri-Rb1 cell growth and increased apoptotic activity in Y79 cells. Increased inhibition of Y79 and Weri-Rb1 cell growth was observed with combination miR-34a and topotecan treatment. mRNA expression changes were observed in 7 of 7 previously reported and 13 of 18 GenMiR++-predicted miR-34a targets after transfection of Y79 cells with miR-34a compared with negative control microRNA. CONCLUSIONS. miR-34a functions as a tumor suppressor in RB cells and is a potential therapeutic target. Differential expression, regulation, and activity of miR-34a in RB cells may suggest further p53 pathway inactivation in RB. (Invest Ophthalmol Vis Sci. 2009; 50: 4542-4551) DOI:10.1167/iovs.09-3520
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