In conclusion, downregulation of miR-124 and miR-383 is a frequent event in MB. Restoration of miR-124 and miR-383 inhibited cell growth and cell cycle progression in MB, suggesting these miRNAs harbor growth suppressor function. In addition, this study demonstrates SLC16A1 and PRDX3 are the direct targets of miR-124 and miR-383, respectively. Together, these data shed new light on miR-124 and miR-383 in MB pathogenesis, and suggest that miR-124/SLC16Al and miR-383/PRDX3 pathways are potential therapeutic targets for treatment of MB. / Medulloblastoma (MB) is an invasive embryonal tumor of the cerebellum, accounting for ∼20% of all primary pediatric brain tumors. The overall survival rate is 60--70% in standard-risk MB patients, but merely ∼30% in high-risk group. Patients who survive often suffer from long-term neurologic and cognitive deficits. New therapy is needed to reduce the mortality rate and to improve the quality of life of survivors. Understanding the molecular pathogenesis of MB is critical to the development of efficacious therapeutic treatment. / MicroRNAs (miRNAs) are short non-protein-coding RNAs that function in diverse biological processes through negative regulation on gene expression at the post-transcriptional level. Accumulative evidence indicates that miRNAs play an important role in the development of human cancers, with their deregulation resulting in altered activity of downstream tumor suppressors, oncogenes and other signaling molecules. / The aim of my project is to identify and characterize deregulated miRNAs located on chromosome 8p in MB. Our group has previously identified a minimally deleted region on 8p22-23.1 and partial or interstitial deletions at 8p22-23.2 in MBs. Despite extensive investigation, no promising candidate genes were identified in these. I questioned if miRNAs (miR-124, miR-383 and miR-320) were the targets on chromosome 8p. Quantitative expression analysis of 29 MBs revealed that miR-124 and miR-383 were downregulated in 72% and 79% of tumors, respectively, compared to normal cerebella. In contrast miR-320 expression was variable. Ectopic expression of miR-124 and miR-383 in MB cell lines (DAOY and ONS-76) showed significant growth inhibition. Cell cycle profiling revealed miR-124 and miR-383 inhibited cell cycle progression and induced apoptosis. These results suggest that miR-124 and miR-383 are potential growth suppressors. / To identify gene targets of miR-124, computational analysis was carried out. Twelve candidate genes predicted as miR124 target were selected for analysis. One candidate gene, SLC16A1, showed downregulation at transcript and protein levels after miR-124 transfection. Luciferase reporter assay demonstrated that miR-124 interacted at the 3' untranslated region of SLC16A1. These results suggest that miR-124 negatively regulates SLC16A1. Expression analysis further revealed that overexpression of SLC16A1 was common in MBs. / To identify miR-383 targets, global gene expression analysis and computational approach were applied. Two genes (PRDX3 and RBMS1 ) showed downregulation upon miR-383 transfection. Reporter assay confirmed that miR-383 interacted at 3' untranslated regions of these genes, suggesting that PRDX3 and RBMS1 are targets ofmiR-383. / Li, Ka Wai Kay. / Source: Dissertation Abstracts International, Volume: 73-06, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 236-293). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344834 |
| Date | January 2011 |
| Contributors | Li, Ka Wai Kay., Chinese University of Hong Kong Graduate School. Division of Anatomical & Cellular Pathology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xxi, 293 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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