Publikationsserver der Universitätsbibliothek Marburg
Titel:Charakterisierung von MUC16 (CA125) Knockdown Varianten einer humanen Ovarialkarzinomzellinie
Autor:Kage, Sophie
Weitere Beteiligte: Wagner, Uwe (Prof. Dr. med. )
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2014/0133
URN: urn:nbn:de:hebis:04-z2014-01337
DOI: https://doi.org/10.17192/z2014.0133
DDC: Medizin
Titel (trans.):Characterisation of MUC16 (CA125) knockdown clones of a human ovarian cancer cell line
Publikationsdatum:2014-01-22
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Tumormarker, Proliferation, CA125, mucin, Koloniebildung, Muzin, Eierstockkrebs, CA125, Apoptosis, MUC16, MUC16, shRNA Knockdown, shRNA knockdown

Zusammenfassung:
Das tumorassoziierte Antigen CA125 (MUC16) wird häufig von Ovarialkarzinomen aber auch anderen epithelialen Tumoren überexprimiert. Obwohl CA125 Serumspiegel häufig zur Verlaufskontrolle von Ovarialkarzinompatientinnen angewendet werden, ist die physi-ologische Funktion dieses Muzins weitgehend unbekannt. Ziel dieser Arbeit war es daher den Einfluss eines MUC16 Knockdowns auf das Wachstum von Ovarialkarzinomzellen zu untersuchen. Nach transienter und stabiler Transfektion der Ovarialkarzinomzelllinie OAW-42H8+ mit MUC16 short hairpin RNA (shRNA) wurden daher Proliferation, Zellzyklus und Apoptoseraten in diesen Zellen analysiert. Daneben wurden zudem Veränderungen hinsichtlich Zelladhäsion, Migration und Invasion in stabilen MUC16 Knockdown Klonen untersucht. Nach transienter Transfektion von OAW-42H8+ mit MUC16 shRNA kam es zu einer sig-nifikante Hemmung des Wachstums durch Induktion einer caspasenabhängigen Apoptose. Dabei konnte eine Aktivierung von Caspase 3 sowie eine vermehrte Spaltung von PARP nachgewiesen werden. Wachstumshemmung und vermehrte Apoptoseraten wurden in stabilen MUC16 Knockdown Klonen so bestätigt. Allerdings zeigte sich hier keine Akti-vierung caspasenabhängiger Signaltransduktionswege mehr. Weder eine signifikante Akti-vierung der Caspase 3 noch eine Spaltung von PARP waren im stabilen MUC16 Knock-down Klon nachweisbar. Die Zellen wurden daher hinsichtlich einer mitochondrialen Frei-setzung von caspasenunabhängigen Faktoren untersucht. In der Tat konnte in stabilen MUC16 Knockdown Klonen eine Translokation von AIF aus dem Mitochondrium in den Zellkern nachgewiesen werden. Zusammenfassend zeigen die Ergebnisse aus transienten und stabilen MUC16 Knockdown Versuchen einen Wechsel von caspasenabhängiger Apoptose hin zu einem caspasenunabhängigem Zelltod nach Langzeitkultivierung des stabilen MUC16 Knockdown Klons der Ovarialkarzinomzelllinie OAW-42H8+. Weiterhin zeigte sich neben einer Proliferationshemmung und Apoptoseinduktion auch eine signifi-kant verminderte Klonogenität nach stabilem MUC16 Knockdown. Da der PI3K/AKT Signalweg in Ovarialkarzinomzellen häufig aktiviert ist und an multiplen zellulären Funk-tionen wie Wachstum, Zellzykluskontrolle und Apoptose beteiligt ist wurde daraufhin der Einfluss von MUC16 auf diesen Signalweg weiter untersucht. Sowohl die Aktivierung von AKT als auch die Expression von AKT waren im stabilen MUC16 Knockdown Klon un-terdrückt. Weiterhin wurden nachgeschaltete Effektormoleküle von AKT wie 4EBP1 und S6, die an der Regulation von Translation und Zellwachstum beteiligt sind, gehemmt. Die verminderte Aktivierung von AKT war zudem mit einer Hemmung des anti-apoptotisch wirksamen Bcl-2 im stabilen MUC16 Knockdown Klon verbunden. Damit beeinflusst MUC16 damit das Zellwachstum in Ovarialkarzinomen durch Interaktion mit dem PI3K/AKT Signalweg, wobei auch andere Signalwege an dieser Regulation beteiligt sein können. Im Gegensatz dazu hatte MUC16 keinen Einfluss auf Migration und Invasion der OAW-42H8+ Zelllinie. Allerdings weist diese Zelllinie generell einen eher unbeweglichen und nichtinvasiven Phänotyp auf, sodass Unterschiede durch MUC16 Knockdown nicht nachweisbar waren. Zusammenfassend nimmt MUC16 eine zentrale Rolle am Überleben von Ovarialkarzi-nomzellen ein. Dabei werden sowohl verschiedene Apoptosesignalwege als auch der PI3K/AKT Signalweg beeinflusst. MUC16 ist damit ein idealer Angriffspunkt für eine zielgerichtete Krebstherapie. Zur Etablierung weiterer Therapieoptionen bedarf es jedoch einer steten Erweiterung des Verständnisses zur physiologischen Funktion und insbesonde-re Interaktion von MUC16 mit den verschiedenen Signalwegen in Ovarialkarzinomen in vitro und in vivo.

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