MicroRNA 128a Increases Intracellular ROS Level by Targeting Bmi-1 and Inhibits Medulloblastoma Cancer Cell Growth by Promoting Senescence |
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Authors: | Sujatha Venkataraman Irina Alimova Rong Fan Peter Harris Nicholas Foreman Rajeev Vibhakar |
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Institution: | 1. Department of Pediatrics, University of Colorado, Denver, Colorado, United States of America.; 2. The Children''s Hospital, Aurora, Colorado, United States of America.; 3. Department of Pediatrics, University of Iowa Children''s Hospital, University of Iowa, Iowa City, Iowa, United States of America.;Roswell Park Cancer Institute, United States of America |
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Abstract: | BackgroundMicroRNAs (miRNAs) are a class of short non-coding RNAs that regulate cell homeostasis by inhibiting translation or degrading mRNA of target genes, and thereby can act as tumor suppressor genes or oncogenes. The role of microRNAs in medulloblastoma has only recently been addressed. We hypothesized that microRNAs differentially expressed during normal CNS development might be abnormally regulated in medulloblastoma and are functionally important for medulloblastoma cell growth.Methodology and Principal FindingsWe examined the expression of microRNAs in medulloblastoma and then investigated the functional role of one specific one, miR-128a, in regulating medulloblastoma cell growth. We found that many microRNAs associated with normal neuronal differentiation are significantly down regulated in medulloblastoma. One of these, miR-128a, inhibits growth of medulloblastoma cells by targeting the Bmi-1 oncogene. In addition, miR-128a alters the intracellular redox state of the tumor cells and promotes cellular senescence.Conclusions and SignificanceHere we report the novel regulation of reactive oxygen species (ROS) by microRNA 128a via the specific inhibition of the Bmi-1 oncogene. We demonstrate that miR-128a has growth suppressive activity in medulloblastoma and that this activity is partially mediated by targeting Bmi-1. This data has implications for the modulation of redox states in cancer stem cells, which are thought to be resistant to therapy due to their low ROS states. |
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