Publikationsserver der Universitätsbibliothek Marburg

Titel:Funktionelle Charakterisierung von BCKDK im Hinblick auf seine Funktion im Pankreaskarzinom
Autor:Hülsemann, Antje Katharina
Weitere Beteiligte: Buchholz, Malte (Prof. Dr.)
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2018/0001
DOI: https://doi.org/10.17192/z2018.0001
URN: urn:nbn:de:hebis:04-z2018-00015
DDC:610 Medizin
Titel (trans.):Functional characterization of BCKDK gene in pancreatic cancer
Publikationsdatum:2018-01-08
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
BCKDK, Pancreatic cancer, Pankreaskarzinom, Pankreaskarzinom, BCKDK, BCKDK

Zusammenfassung:
Das duktale Adenokarzinom des Pankreas (PDAC) zeichnet sich durch eine hohe Mortalität aus: die Fünf-Jahres-Überlebensrate liegt bei nur 8%. Ursächlich hierfür ist zum einen die späte Diagnose aufgrund fehlender Frühsymptome, sodass der Tumor bei Erstdiagnose oftmals schon metastasiert und eine operative Entfernung nicht möglich ist. Zum anderen zeigen sich Pankreaskarzinome äußerst resistent gegen eine chemotherapeutische Behandlung. Nach dem derzeitigen Stand der Forschung entsteht das PDAC aus Vorläuferläsionen durch eine Akkumulation charakteristischer Genmutationen. Die genauen molekularpathologischen Mechanismen sind jedoch noch nicht verstanden. Dementsprechend wurde in den letzten Jahren intensiv nach Proteinen gesucht, die eine wichtige Rolle in der Pathogenese des Pankreaskarzinoms spielen und somit Angriffspunkte für neue Therapien darstellen. Eines dieser Proteine ist die Branched-Chain α-Ketoacid Dehydrogenase-Kinase (BCKDK). In einem Kinom-Screening zeigte sich nach Repression von BCKDK in Pankreaskarzinomzellen eine erhöhte Apoptoserate. Zudem konnte eine vermehrte Expression des BCKDK-Gens in primären humanen Pankreaskarzinomgeweben nachgewiesen werden. Die BCKDK reguliert die Branched-Chain α-Ketoacid Dehydrogenase und ist somit ein Schlüsselenzym im Abbau verzweigtkettiger Aminosäuren. Eine weitere Funktion der Kinase ist bisher nicht beschrieben. Im Rahmen dieser Arbeit wurde die möglicherweise pro-onkogene Wirkung der BCKDK im PDAC näher untersucht. Hierzu wurde die Expression der Kinase mithilfe dreier siRNAs (siRNA 1, 3 und 5) in zwei Pankreaskarzinomzelllinien supprimiert und jeweils die Auswirkungen auf Apoptose, Proliferation und Expression von Zielproteinen untersucht. Die Versuchsreihen lieferten unterschiedliche Ergebnisse. Die Verwendung der siRNA 1 führte in beiden Zelllinien zu einer Abnahme der Zellviabilität. Als Ursache hierfür konnte eine Apoptoseinduktion nachgewiesen werden. Zusätzlich sank die Proliferationsrate und es kam zu einem Zellzyklusarrest der Zellen in der G2-Phase. Die Repression des Zielgens mit der siRNA 3 führte ebenfalls zu einer Abnahme der Zellviabilität durch Apoptoseinduktion, es kam jedoch nur in einer der verwendeten Zelllinien zu einer signifikanten Abnahme der Proliferationsrate. Die Zellen, die mit der siRNA 5 transfiziert worden waren, blieben hingegen sowohl in der Zellviabilität als auch in der Proliferation im Vergleich zur Kontrolle unverändert. Diese sehr unterschiedlichen Versuchsergebnisse sind möglicherweise durch Off-Target-Effekte der siRNAs zu erklären. Die zugrundeliegenden molekularpathologischen Mechanismen konnten in der vorliegenden Arbeit jedoch nicht vollständig aufgedeckt werden und bedürfen weiterer Analysen.

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