Dokument: Molekulare und funktionelle Untersuchungen zur Rolle von miR-16-5p und miR-15a-5p in der Pathogenese maligner Gliome
| Titel: | Molekulare und funktionelle Untersuchungen zur Rolle von miR-16-5p und miR-15a-5p in der Pathogenese maligner Gliome | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=38813 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20160627-113533-1 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Forchmann, Anneliese [Autor] | |||||||
| Dateien: |
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| Stichwörter: | MiR-16-5p, miR-15a-5p, Glimme, miRNAs | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibungen: | MicroRNAs (miRNAs) are short, single stranded, non-coding RNA molecules which regulate gene expression by destabilization of the mRNA and/or inhibition of translation. Aberrant expression of miRNAs has been implicated in the pathogenesis of various types of cancer including gliomas. In former work during my master thesis, I detected decreased miR‑16‑5p expression levels relative to non-neoplastic brain tissue in diffuse and anaplastic astrocytomas as well as secondary glioblastomas and a subset of primary glioblastomas. Following up on this finding, I found that expression of miR‑16‑5p and its family member miR‑15a‑5p, which map together at chromosome band 13q14.2, was lower in isocitrate dehydrogenase 1 or 2 (IDH1/2) mutant as compared to IDH1/2 wildtype gliomas, and consistently down-regulated in established glioma cell lines. Functional studies revealed that overexpression of miR‑16‑5p or miR‑15a‑5p precursors inhibited viability and proliferation and increased apoptosis of glioma cells. In silico analysis showed binding sites for miR‑16‑5p and miR‑15a‑5p in the 3'-untranslated region of transcripts encoding CDK6, CDC25A, CCND3, CCNE1, WEE1, CHK1, BCL2 and MCL1. Overexpression of miR‑16‑5p or miR‑15a‑5p precursor molecules in glioma cells resulted in down-regulation of CDK6, CDC25A, Cyclin D3, Cyclin E1, WEE1, CHK1, BCL2 and MCL1. While CDK6, CDC25A, Cyclin D3, Cyclin E1 and BCL2 are already experimentally validated miR‑16‑5p targets, I could additionally prove that both miR‑16‑5p and miR‑15a‑5p directly bind to the 3'-untranslated region of transcripts encoding WEE1, CHK1 and MCL1. In line with the in vitro data, CDK6, WEE1, CHK1 and MCL1 mRNA levels were significantly increased in malignant glioma tissues when compared to non-neoplastic brain tissue. To investigate potential mechanisms leading to down-regulation of miR‑16‑5p and miR‑15a‑5p in glioma cells, siRNA knock-down experiments for MYCC and HDAC3 were performed. Furthermore, glioma cells were treated with the histondeacetylase (HDAC)-inhibitor Trichostain A (TSA). These experiments revealed that trichostatin A treatment as well as MYCC and HDAC3 knockdown significantly increased expression of miR‑16‑5p, miR‑15a‑5p and their host gene DLEU2 in glioma cells. Taken together, the experimental results summarized in this thesis suggest an important role of miR‑16‑5p and miR‑15a‑5p down-regulation in the pathogenesis of astrocytic gliomas by facilitating up-regulation of several pro-proliferative and anti-apoptotic proteins. Similar to findings reported in lymphatic tumors, the own data suggest that the observed transcriptional repression of miR‑16‑5p in astrocytic gliomas is related to increased MYCC and HDAC3 expression as well as histone modifications.MicroRNAs (miRNAs) sind kurze, einzelsträngige, nicht-kodierende RNA-Moleküle, die die Genexpression durch die Destabilisierung der mRNA und/oder Inhibierung der Translation regulieren. Veränderungen der miRNA-Expression wurden in zahlreicher Tumorarten, darunter auch maligne Gliome gefunden. In eigenen Voruntersuchungen im Rahmen der Masterarbeit fand sich eine Herrunterregulierung der Expression von miR‑16‑5p in diffusen und anaplastischen Astrozytomen, sekundären Glioblastomen sowie einem Teil der primären Glioblastome im Vergleich zu nicht-neoplastischem Hirngewebe, die mittels Reverser stem-loop Trankriptions-PCR detektiert wurde. Des Weiteren war die Expression von miR‑16‑5p und der auf Chromosom 13q14.2 kolokalisierten miR‑15a‑5p geringer in den Gliomen, die eine Mutation im Isocitrate dehydrogenase 1 oder 2 (IDH1/2)-Gen hatten. Außerdem war die miR‑16‑5p und miR‑15a‑5p Expression in etablierten Gliomzelllinien signifikant herrunterreguliert. Eine transiente Überexpression von Vorläufermolekülen der miRNA miR‑16‑5p oder miR‑15a‑5p, welche die gleiche Bindungsspezifität aufweisen, reduzierte einerseits die Viabilität- und Proliferationsrate und induzierte andererseits die Apoptoseaktivität von Gliomzellen relativ zu Kontroll-transfizierten Zellen. In silico-Analysen sagten Bindestellen für miR‑16‑5p und miR‑15a‑5p in der 3´-UTR von mehreren Genen vorraus, deren Genprodukte in der Regulation des Zellzyklus und der Apoptose von entscheidender Bedeutung sind, darunter CDK6, CDC25A, CCND3, CCNE1, WEE1, CHK1, BCL2 und MCL1. Überexpression von miR‑16‑5p oder miR‑15a‑5p Vorläufermolekülen in Gliomzellen führte zu einer signifikant erniedrigten Expression von CDK6, CDC25A, Cyclin D3, Cyclin E1, WEE1, CHK1, BCL1 und MCL1. Während CDK6, CDC25A, CCND3, CCNE1, WEE1, CHK1 und BCL2 in der Literatur bereits als direkte Targets von miR‑16‑5p beziehungsweise miR‑15a‑5p beschrieben wurden, konnten in eigenen Experimenten zudem die direkte Bindung dieser miRNAs in der 3´-UTR von WEE1, CHK1 und MCL1 mittels Luciferase-Assays gezeigt beziehungsweise validiert werden. Konform mit den in vitro Daten zeigten die Gene CDK6, WEE1, CHK1 und MCL1 eine im Vergleich zu nicht-neoplastischem Hirngewebe erhöhte mRNA-Expression in astrozytären Gliomen. Um die Herrunterregulierung von miR‑16‑5p respektive miR‑15a‑5p in Gliomzellen zu untersuchen, wurden siRNA-mediierte Knock-down-Experimente für die Gene MYCC und HDAC3 durchgeführt. Des Weiteren wurden Gliomzellen mit dem Histondeazetylase (HDAC)-Inhibitor Trichostatin A (TSA) behandelt. Diese Experimente zeigten, dass sowohl der Knock-down von MYCC oder HDAC3 als auch eine TSA-Behandlung der Zellen zu einer signifikant erhöhten Expression von miR‑16‑5p und miR‑15a‑5p als auch deren Wirtsgen DLEU2 in Gliomzellen führten. Zusammenfassend sprechen die erzielten Ergebnisse dafür, dass miR‑16‑5p und miR‑15a‑5p eine wichtige Rolle in der Pathogenese von astrozytären Gliomen durch die direkte Regulation multipler Regulatoren von Zellzyklus und Apoptose spielen. Zusätzlich ergab sich analog zu Befunden in lymphatischen Tumoren Evidenz dafür, dass für die beobachtete transkriptionelle Repression von miR‑16‑5p in IDH1-mutierten astrozytären Gliomen inhibitorische Einflüsse von MYCC und HDAC3 sowie Histonmodifikationen von Bedeutung sind. | |||||||
| Quelle: | miRBase. Online verfügbar unter http://www.mirbase.org/, zuletzt geprüft am 06.11.2014.
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie | |||||||
| Dokument erstellt am: | 27.06.2016 | |||||||
| Dateien geändert am: | 27.06.2016 | |||||||
| Promotionsantrag am: | 25.05.2016 | |||||||
| Datum der Promotion: | 21.06.2016 |
