Publikationsserver der Universitätsbibliothek Marburg
Titel:Mechanismen der NFATc1-abhängigen Regulation von Stammzelleigenschaften im Pankreaskarzinom
Autor:Vogt, Sophia
Weitere Beteiligte: Ellenrieder, Volker (Prof. Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0378
DOI: https://doi.org/10.17192/z2016.0378
URN: urn:nbn:de:hebis:04-z2016-03781
DDC: Medizin
Titel (trans.):Mechanisms of NFATc1-dependent regulation of stem cell characteristics in the pancreas carcinoma
Publikationsdatum:2016-06-16
Lizenz:https://creativecommons.org/licenses/by/4.0

Dokument

Schlagwörter:
Stammzelleigenschaften, Chemoresistenz, Stammzelle, NFAT, chemoresistance, Sox2, Stemness, Protein p53, Bauchspeicheldrüsenkrebs, pancreatic cancer

Zusammenfassung:
Die infauste Prognose des Pankreaskarzinoms ist vor allem dem aggressiven Wachstumsverhalten und der ausgeprägten Resistenz gegenüber konventionellen Chemotherapeutika geschuldet. Beide Charakteristika sind mit einer Entdifferenzierung des Tumors und der Aneignung von Stammzelleigenschaften assoziiert. Die Transformation in stammzellartige Tumorzellen geht mit der Aktivierung spezifischer Gensignaturen und der Induktion von Stammzellfaktoren (Sox2, Klf4, Oct4, Nanog und Bmi1) einher. Ein zentrales Ereignis der Entdifferenzierung und Aneignung von Stammzelleigenschaften ist der Verlust des Tumorsuppressors p53, der in 75 % aller humanen Pankreaskarzinome beobachtet wird. Das trifft in besonderem Maße auf Tumore mit Aktivierung des onkogenen Transkriptionsfaktors NFATc1 zu, der ebenfalls in der Mehrzahl humaner Pankreaskarzinome exprimiert wird und das Wachstum und Metastasierungsverhalten von Tumoren moduliert. Im Mittelpunkt dieser Arbeit stand die Regulation von Stammzelleigenschaften im Pankreaskarzinom durch einen bislang nicht beschriebenen und antagonistisch wirkenden p53-NFATc1- Signalweg. Wir konnten zeigen, dass die Funktion von NFATc1 im Pankreaskarzinom durch p53 definiert wird und dass der Verlust von p53 über NFATc1-abhängige Aktivierung des Stammzellfaktors Sox2 (und anderer Stammzellfaktoren) sowohl in vivo als auch in vitro die Ausbildung von Stammzelleigenschaften begünstigt. Dabei induziert NFATc1 die Expression von Sox2 durch direkte Bindung an Promotor und Enhancer sowie gleichzeitige Rekrutierung der RNA-Polymerase II. Die NFATc1-Sox2-vermittelte Aneignung von Stammzelleigenschaften setzt eine Hemmung des hierarchisch dominanten p53-microRNA-200c-Signalweges voraus, der die Aktivierung von Sox2 und anderer Stammzellfaktoren unterdrückt. Zusammenfassend tragen die Ergebnisse dieser Arbeit zu einem besseren Verständnis der molekularen Mechanismen der Tumorprogression im Pankreaskarzinom bei und zeigen, dass zentrale Aspekte der zellulären Plastizität und Regulation von Stammzelleigenschaften durch ein hierarchisch angelegtes Netzwerk kontrolliert werden. Die Erkenntnis, dass der häufige Verlust von p53 durch Aktivierung des NFATc1-Sox2-Signalweges zur Ausbildung von Stammzelleigenschaften führt, eröffnet möglicherweise neue und zielgerichtete Ansätze in der Behandlung des Pankreaskarzinoms.

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