Dokument

Zusammenfassung:
Das Neuroblastom ist ein Tumor des Säuglings- und Kindesalters. Es entsteht aus Vorläuferzellen des sympathischen Nervensystems, den Neuroblasten. Das klinische Erscheinungsbild reicht von sehr langsam verdrängend wachsenden Tumoren, die das Potential einer vollständigen Rückbildung ohne Therapie besitzen, bis zu aggressiven invasiv wachsenden Tumoren, deren 5-Jahres-Überlebenswahrscheinlichkeit bei Ausnutzung aller zur Verfügung stehenden Therapieoptionen lediglich 30% beträgt. Die großen Unterschiede im biologischen Verhalten der Tumore basieren auf molekulargenetischen Risikofaktoren. Einer dieser Risikofaktoren ist die Amplifikation des Protoonkogens MYCN. Das exprimierte Protein N-Myc ist ein Transkriptionsfaktor, der andere Gene aktivieren und das Wachstum der Zelle beeinflussen kann. Es sind viele Zielgene des N-Myc-Proteins bekannt. Diese Kenntnisse reichen jedoch nicht aus um die N-Myc-induzierte Tumorentstehung sowie das besonders aggressive Wachstum und die schlechte Prognose der MYCN-amplifizierten Tumore zu erklären. Um weitere Gene zu identifizieren, die für das Wachstum der MYCN-amplifizierten Tumore essentiell sind, wurde ein Screen durchgeführt. Dabei wurden jeweils 194 Gene in einer MYCN-amplifizierten Neuroblastomzelllinie und einer Zelllinie ohne MYCN-Amplifikation ausgeschaltet. Alle Gene, die in der MYCN-amplifizierten Zelllinie einen Wachstumsarrest auslösten, für die nicht amplifizierte Zelllinie hingegen verzichtbar waren, wurden gelistet. Die Bedingungen wurden von 17 Genen erfüllt. In der vorliegenden Arbeit konnte gezeigt werden mit welcher Effektivtät die Expression der einzelnen Gene im Screen herunterreguliert wurde. Dies ist notwendig um die Anzahl der tatsächlich untersuchten Gene abschätzen zu können. Unter den 17 entdeckten Genen befindet sich die Aurora-Kinase A. Wird Aurora-A inhibiert bleiben die MYCN-amplifizierten Zellen im Wachstum zurück. Um zu überprüfen, ob der beobachtete Effekt nicht nur zelllinienspezifisch ist, sondern generelle Gültigkeit besitzt und auf andere Zelllinien und Neuroblastome übertragbar ist, wurden verschiedene Zelllinien auf dieses Verhalten bei Aurora-A-Depletion überprüft. In vier MYCN-amplifizierten und vier nicht amplifizierten Zelllinien bestätigten sich die Beobachtungen. Darüber hinaus konnte in den acht Neuroblastomzelllinien durch Untersuchung der Proteinveränderungen in der Zelle bei Aurora-A-Depletion auf den möglichen Mechanismus, auf dem die Beobachtungen des Wachstumsarrests beruhen, geschlossen werden. Aurora-A stabilisiert N-Myc und ist somit maßgeblich am Wachstum der Zelle beteiligt. Im Gegenzug dazu führt die Aurora-A-Depletion zu erniedrigten N-Myc-Spiegeln in der Zelle und begünstigt somit den Wachstumsarrest. Aurora-A-Kinase konnte als wichtiger Regulator der N-Myc-Stabilität identifiziert und seine entscheidende Bedeutung bei der Entstehung der MYCN-amplifizierten Neuroblastome geklärt werden.

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