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Originally published In Press as doi:10.1167/iovs.09-3520 on May 14, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:4542-4551.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3520
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Differential MicroRNA-34a Expression and Tumor Suppressor Function in Retinoblastoma Cells

Clifton L. Dalgard,1 Marco Gonzalez,2 Jennifer E. deNiro,2 and Joan M. O'Brien1

1From the Ocular Oncology Unit, Department of Ophthalmology, and 2School of Medicine, University of California at San Francisco, San Francisco, California.

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.






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