Dokument

Zusammenfassung:
Das duktale Adenokarzinom des Pankreas stellt heute immer noch eines der aggressivsten und am schlechtesten behandelbaren Malignome dar. Deshalb ist es umso wichtiger, Genetik und Pathomechanismen dieser Erkrankung im Detail aufzuklären und Marker zur Früh- bzw. Differenzialdiagnose sowie potentielle Ziele für targeted therapies zu finden. Mit Hilfe von enzymatisch generierten, Transkriptom-basierten shRNA-Bibliotheken konnten in Hochdurchsatzanalysen potentielle Onko- bzw. Tumorsuppressorgene in PDAC identifiziert werden. NPC2 wurde als eines dieser potentiellen Onkogene für weitere funktionelle Assays im Bezug auf Zellvitalität, -proliferation und -motilität ausgewählt. Expressionsanalysen auf mRNA-Ebene zeigten eine deutliche Überexpression des Gens sowohl in pankreatischem Tumorgewebe als auch in verschiedenen Pankreaskarzinomzelllinien. Von vier in dieser Arbeit untersuchten Zelllinien zeigte sich nach siRNA-vermitteltem Knockdown jedoch nur in BxPC3-Zellen ein akuter funktioneller Effekt im Sinne einer hoch signifikanten Abnahme der Zellvitalität. Dieser wachstumsfördernde Effekt von NPC2 lässt sich nicht auf das Pankreaskarzinom im Allgemeinen übertragen. Die Zellproliferation und –motilität waren nach transienter Repression von NPC2 im Kurzzeit-Versuch nicht beeinträchtigt. Auch das Gen ADRBK1 wurde in einem Hochdurchsatz-Screening, welches auf Pankreaskarzinom-spezifischen cDNA-Microarrays und dem Prinzip der reversen Transfektion basierte, identifiziert. ADRBK1 zeigte eine zeitabhängige Translokation in den Nukleus und es stellte sich die Frage, ob die Kinase eine direkte Rolle bei der Genregulation spielt. Vorversuche der Arbeitsgruppe zeigten zudem, dass ADRBK1 im humanen PDAC nicht nur signifikant überexprimiert wird, sondern auch pro- proliferative Effekte vermittelt. Rekombinante Überexpression der Kinase beschleunigte das Zellwachstum, während ihr Knockdown dieses signifikant inhibierte. Als Ursache für die beobachtete Wachstumshemmung kamen potentiell die Induktion eines Zellzyklusarrests oder Apoptose in Frage. Die daraufhin von mir im Western-Blot untersuchten Proteinlevel von CDKN1A/p21, CDKN1B/p27, Cyclin A, Cyclin D1, pRB und c-myc waren nach ADRBK1-Repression jedoch unverändert. Eine Spaltung der Apoptosemarker PARP und Caspase 3 war nur in der Zelllinie PaTu-8988t nachweisbar. Somit kann weder die Induktion von Apoptose noch ein Zellzyklusarrest als maßgebliche Ursache der Wachstumsabnahme nach ADRBK-Knockdown gelten. Um die Bedeutung des Gens für PDAC weiter aufzuklären, sollte die nukleäre Translokation und deren potentielle Auswirkungen auf die Genfunktion weiter untersucht werden. Zudem sollten zelluläre Zielproteine von ADRBK1, die Relevanz der Kinase beim Zusammenspiel von Krebszellen mit infiltrierenden Immunzellen und ihre Rolle bezüglich der Zellmotilität identifiziert werden.

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