Publikationsserver der Universitätsbibliothek Marburg

Titel:Charakterisierung des STAT3-Signalwegs in der NFATc1-abhängigen Genese und Progression des Pankreaskarzinoms
Autor:Brunner, Marius
Weitere Beteiligte: Ellenrieder, Volker (Prof. Dr. med.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0454
URN: urn:nbn:de:hebis:04-z2016-04547
DOI: https://doi.org/10.17192/z2016.0454
DDC: Medizin
Titel (trans.):Characterisation of the STAT3-pathway in the NFATc1-dependant development and progression of pancreatic carcinomas
Publikationsdatum:2016-07-19
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
Enhancer, Pankreaskarzinom, NFAT, Stroma, PDAC, Promotor, Tumor, NFATc1, ADM, KRAS, epigenetic, STAT3, RCAN1, pancreatic carcinoma, PanIN, Enhancer, STAT3, NFAT, Epigenetik

Zusammenfassung:
Das duktale Adenokarzinom des Pankreas zählt zu den aggressivsten soliden Tumoren und ist durch eine ausgeprägte Resistenz gegenüber Standardchemotherapeutika sowie eine infauste Prognose gekennzeichnet. Detaillierte Untersuchungen der zugrunde lie-genden Mechanismen beschreiben eine zentrale Rolle inflammatorischer Signalwege in der Karzinogenese und Progression des Pankreaskarzinoms. In Vorarbeiten konnte un-sere Arbeitsgruppe den inflammatorischen Transkriptionsfaktor NFATc1 als wichtiges Onkogen in der Entzündungs-assoziierten Pankreaskarzinogenese identifizieren. Mole-kulare Analysen in diversen in vitro und in vivo Modellen des Pankreaskarzinoms erga-ben darüber hinaus, dass NFATc1 in einem hohen Prozentsatz humaner Pankreaskar-zinome überexprimiert wird und funktionell mit dem inflammatorischen Transkriptions-faktor STAT3 interagiert, um onkogene Gensignaturen während der Progression des Pankreaskarzinoms zu kontrollieren. Ziel dieser Arbeit war es, den Mechanismus der NFATc1:STAT3-abhängigen Genregu-lation genauer zu untersuchen und die Komplexbildung beider Partner an der DNA zu charakterisieren. Weiterhin sollte die biologische Relevanz eines konditionalen STAT3-Verlusts im Kontext einer pankreasspezifischen KRASG12D- sowie NFATc1-Aktivierung in einem transgenen Mausmodell in vivo analysiert werden. Die im Rahmen der vorliegenden Arbeit gewonnen Daten zeigen, dass die NFATc1-ab-hängige transkriptionelle Regulation onkogener Gensignaturen die Bindung des Tran-skriptionsfaktors an Enhancerregionen ausgewählter Zielgene voraussetzt. Im Gegen-satz dazu identifizierten ChIP-Analysen das NFATc1-Partnerprotein STAT3 an den je-weiligen Promotoren NFATc1-kontrollierter Zielgene. Darüber hinaus werden sowohl die NFATc1-Bindung an dessen Zielgenen sowie deren transkriptionelle Aktivierung durch NFATc1 maßgeblich von der Aktivität des IL-6-STAT3-Signalwegs determiniert. Diese Ergebnisse suggerieren eine Enhancer-Promotor-Loop-Formation als Mechanismus der Transkriptionskontrolle onkogener Signaturen durch NFATc1:STAT3 Komplexe. Um die biologische Relevanz dieser Interaktion in vivo zu untersuchen, wurde ein trans-genes Mausmodell generiert, das zusätzlich zu den konstitutiven Aktivierungen von KRASG12D und NFATc1 einen Verlust der STAT3-Expression im Pankreas aufweist. Diese Mäuse zeigten entgegen der Erwartungen eine beschleunigte Pankreaskarzinom-progression und eine deutlich verringerte mittlere Überlebenszeit von nur 60 Tagen gegenüber ihren Wurfgeschwistern ohne pankreasspezifischen STAT3-Verlust. Morpholo-gisch waren die Pankreaskarzinome STAT3-defizienter Mäuse durch eine ausgeprägte Zunahme des stromalen Tumoranteils gekennzeichnet. Diese Arbeit unterstreicht die onkogenen Funktionen von NFATc1 in der Karzinogenese und Progression des Pankreaskarzinoms und identifiziert die Komplexbildung mit STAT3 als zentralen transkriptionellen Mechanismus für die Kontrolle onkogener Gensignaturen im inflammations-assoziierten Pankreaskarzinom. Trotz der Charakterisierung von NFATc1 als vielversprechende Zielstruktur in der Behandlung des Pankreaskarzinoms existieren bis dato keine therapeutischen Strategien, die eine spezifische pharmakologi-sche Inhibition von NFATc1 in der Tumorzelle ermöglichen. Vor dem Hintergrund erfolgsversprechender Daten einer aktuellen klinischen Studie zur Inhibition des Jak/STAT3-Signalwegs in der Therapie des Pankreaskarzinoms und der hier beschriebenen zentralen Funktion von STAT3 in der NFATc1-abhängigen Tran-skriptionskontrolle erscheint die pharmakologische Inhibition des NFATc1-Partnerpro-teins STAT3 ein vielversprechender indirekter therapeutischer Ansatz für die Blockade der NFATc1-vermittelten Tumorprogression zu sein. Die beschleunigte Tumorprogres-sion im STAT3-defizienten in vivo Modell auf der Basis einer konstitutiven NFATc1-Akti-vierung hingegen deutet darauf hin, dass eine Inhibition des Jak/STAT3-Signalwegs v.a. in NFATc1-negativen Pankreaskarzinomen wirksam sein könnte und unterstreicht somit die Notwendigkeit der molekularen Stratifizierung für die Therapie dieser heterogenen Tumorerkrankung.

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