Publikationsserver der Universitätsbibliothek Marburg

Titel:Expression HIF-1-abhängiger Gene in humanen Lungenadenokarzinom (A549)-Zellen und deren Regulation nach Photonen- und Schwerionenbestrahlung
Autor:Bill, Verena Maria
Weitere Beteiligte: Engenhart-Cabillic, R. (Prof. Dr.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0698
DOI: https://doi.org/10.17192/z2013.0698
URN: urn:nbn:de:hebis:04-z2013-06987
DDC: Medizin
Titel (trans.):Role of Hypoxia-inducible factor-1 and its target genes in human lung adenocarcinoma cells after photon- versus carbon ion irradiation
Publikationsdatum:2013-12-04
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
Bestrahlung, Photon Irradiation

Zusammenfassung:
Hypoxische Tumorzellen sind besonders unsensibel für Photonenbestrahlung. Der Hypoxie–induzierbare Faktor (HIF-1), dessen Rolle nach Schwerionenbestrahlung noch unklar ist, wird als eine der wesentlichen Ursachen für die Radioresistenz gegenüber der konventionellen Photonenbestrahlung angesehen. Ziel dieser Arbeit war das zelluläre Überleben und die Regulation von HIF-1 und dessen Zielgenen nach beiden Bestrahlungsqualitäten unter verschiedenen Sauerstoffbedingungen an humanen nichtkleinzelligen Bronchialkarzinom-Zellen (A549) zu untersuchen. Hierzu wurde mit biologisch äquivalenten Dosen das im Koloniebildungstest bestimmten 10% Überleben (D10), für Photonen [6 Gy] und Schwerionen [2 Gy] bestrahlt. Die Ergebnisse des zellulären und klonogenen Überlebens belegten die unter Hypoxie beschriebene Resistenz gegenüber Photonenbestrahlung. Das Überleben hypoxischer gegenüber normoxischer A549-Zellen nach Schwerionenbestrahlung war jedoch nicht erhöht. Reoxygenierte Zellen zeigten kein erhöhtes Überleben nach Photonenbestrahlung. In den Genexpressionsanalysen hatte sich neben der sauerstoffabhängigen Regulation HIF-1-abhängiger Zielgene auch eine vermehrte Expression von GLUT-1, LDH-A, PDK-1 und VEGF durch Photonenbestrahlung nicht aber durch Schwerionenbestrahlung nach 48 h in normoxischen Zellen gezeigt. CDKN1A, der als Inhibitor der Zellzyklusprogression erwartungsgemäß nach Bestrahlung stark exprimiert wurde, zeigte auch eine sauerstoffabhängige Regulation. Für GLUT-1 und HIF-1 stellte sich im Western Blot und einer anschließenden Densitometrie eine signifikante Steigerung durch Hypoxie dar, nach Photonenbestrahlung ließ sich ein Trend zur Expressionssteigerung erkennen und Schwerionenbestrahlung bewirkte keine Expressionsänderung. Auf Proteinebene zeigte sich nach 72 h eine signifikante Steigerung von VEGF durch Photonenbestrahlung in normoxischen Zellen. Die aktuell vermehrt auftretende Diskussion, dass SCF oder Trx-1 in Zusammenhang mit HIF-1 steht, ließ sich unter gegebenen Versuchsbedingungen für A549-Zellen nicht bestätigen. Während Trx-1 weder durch veränderten Sauerstoffgehalt noch durch Bestrahlung an den untersuchten Zeitpunkten in seiner Expression beeinflusst wurde, zeigte sich für SCF sowohl in der quantitativen Real Time-PCR als auch im ELISA eine vermehrte Expression nach Photonenbestrahlung, nicht jedoch nach Schwerionenbestrahlung. Zusammenfassend lässt sich annehmen, dass HIF-1 nach Photonenbestrahlung vermehrt aktiviert wird und somit Anteil an der Radioresistenz trägt, wohingegen HIF-1 bzw. dessen Zielgene nach Schwerionenbestrahlung nicht vermehrt exprimiert werden. Darin scheint ein weiterer wichtiger Unterschied zwischen Photonen- und Schwerionenbestrahlung zu liegen. Aufgrund der Assoziation von HIF-1 mit einer schlechten Prognose stellt der Einsatz von Schwerionenbestrahlung einen möglichen Vorteil für Schwerionenbestrahlung bei der Behandlung des nicht-kleinzelligen Bronchialkarzinoms dar, was klinisch zu beweisen wäre.

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