Publikationsserver der Universitätsbibliothek Marburg

Titel:Die Rolle der Überexpression von PRMT1 im duktalen Adenokarzinom des Pankreas
Autor:Zeller, Marc
Weitere Beteiligte: Bauer, Uta-Maria (Prof.Dr.)
Veröffentlicht:2015
URI:https://archiv.ub.uni-marburg.de/diss/z2015/0155
URN: urn:nbn:de:hebis:04-z2015-01551
DOI: https://doi.org/10.17192/z2015.0155
DDC: Medizin
Titel (trans.):The role of PRMT1 overexpression in pancreatic ductal adenocarcinoma
Publikationsdatum:2015-03-09
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Gli1, anchorage-independent growth, Arginin-Methyltransferase, Proliferation, Überexpression, PRMT1, Gli1, ankerunabhängiges Wachstum, c-MYC, c-MYC, Bauchspeicheldrüsenkrebs, Genexpression, Immuncytochemie, Microarray, Arginin-Methyltransferase, PRMT1

Zusammenfassung:
Das Ziel dieser Arbeit war die Untersuchung der Rolle von PRMT1 im humanen duktalen Adenokarzinom des Pankreas. Ausgangspunkt hierzu war eine Veröffentlichung, die eine Überexpression von PRMT1 auf Transkriptebene im PDAC relativ zu gesundem Gewebe zeigte. Als erste Aufgabe wurde in der vorliegenden Arbeit der Frage nachgegangen, ob auch eine Erhöhung der Proteinspiegel von PRMT1 im PDAC-Gewebe vorliegt. Durch Vorarbeiten im Labor und im Rahmen dieser Arbeit konnte diese Fragestellung durch immunhistochemische Färbungen von Pankreasschnitten positiv beantwortet werden. Um eine potenzielle Funktion dieser verstärkten PRMT1-Expression im PDAC zu untersuchen, wurde die Proliferationsfähigkeit der PDAC-Zelllinien Panc1 und MiaPaCa2 mittels Wachstumskurven bestimmt. Durch siRNA-vermittelte Depletion von PRMT1 in diesen Zellen wurde deutlich, dass das Protein für die Proliferationsfähigkeit essenziell ist. Diese Erkenntnis ließ sich durch eine Wiederholung des Experiments in HeLa-Zellen auch auf weitere Tumorzellen ausweiten. Zudem wurde die Fähigkeit von PDAC-Zellen zum ankerunabhängigen Wachstum in Soft-Agar-Assays untersucht. Nach Depletion von PRMT1 war diese Fähigkeit gehemmt. In einem weiteren Teil dieser Arbeit wurden zuvor erbrachte Ergebnisse der Arbeitsgruppe bezüglich einer Assoziation des Transkriptionsfaktors GLI1 mit PRMT1 einer Validierung und weiteren Bearbeitung unterzogen. Mit Hilfe von Expressionsanalysen auf Transkriptebene konnten keine belastbaren Hinweise auf einen Einfluss von PRMT1 auf die GLI1-Spiegel festgestellt werden. Eine Interaktion der beiden Proteine konnte weder in vivo noch in vitro nachgewiesen werden und eine Methylierung von GLI1 durch PRMT1 konnte nicht abschließend verifiziert werden. Eine Rolle von PRMT1 bei der Koaktivierung der GLI1-abhängigen Genexpression bleibt fraglich und bedarf weiterer Untersuchungen. Dem Transkriptionsfaktor c-MYC wurde in Veröffentlichungen eine steigernde Wirkung auf die Expressionsrate von PRMT1 im Zuge von Entwicklungsprozessen nachgewiesen. In der vorliegenden Arbeit wurde geprüft, ob dieser Mechanismus auch in Zellen des PDAC existiert. Mit Hilfe von c-MYC-Depletionen konnte bestätigt werden, dass in diesem System ebenfalls eine Regulation der Expression von PRMT1 durch c-MYC sowohl auf Transkript- als auch auf Proteinebene stattfindet. Durch Hybridisierung eines Oligonukleotid-Microarrays wurde der Einfluss von PRMT1 auf das Transkriptom von Panc1-PDAC-Zellen analysiert. Von den 51 erhaltenen Kandidatengenen, die unter siRNA-vermittelter PRMT1-Depletion mehr als zweifach in ihrer Expression reguliert waren, konnten bisher zwei Gene validiert werden. Für die Proteine GLIPR1 und ANXA8, die von diesen Genen kodiert werden, wurden in verschiedenen Publikationen bereits tumorrelevante Funktionen nachgewiesen. Die weitere funktionelle Charakterisierung dieser Proteine im PDAC wird eine der Aufgaben im künftigen Verlauf des Projekts sein.

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