Expression HIF-1-abhängiger Gene in humanen Lungenadenokarzinom (A549)-Zellen und deren Regulation nach Photonen- und Schwerionenbestrahlung
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Abstract
Exposed to hypoxia tumor cells are notably resistant to photon irradiation. The hypoxiainducible
transcription factor 1α (HIF-1α) seems to play a fundamental role in this
resistance, while its role after heavy-ion beam remains unknown. The intention of this
study was to determine how A549-cells (non-small-cell lung carcinoma) react in
different oxygenation states after irradiation with photons or heavy ions, particularly in
regards to their expression of HIF-1 target genes.
Resistance of hypoxic A549 cells after photon irradiation was documented by cellular
and clonogenic survival. In contrast, cellular survival after heavy-ion irradiation in
hypoxic cells was not elevated to normoxic cells. Among the oxygen dependent
regulation of HIF-1 target genes, gene expression analyses showed an increased
expression of GLUT-1, LDH-A, PDK-1 and VEGF after photon irradiation but not after
heavy-ion irradiation after 48 hours in normoxic cells. As expected, CDKN1A as
inhibitor of cell cycle progression showed higher expression after both radiation forms;
interestingly CDKN1A was also in an oxygen dependent manner lightly upregulated. In
western blot analyses we demonstrated a significant increase of HIF-1 and GLUT-1
caused by hypoxia, but only a tendency of increased protein level in hypoxia after
photon irradiation and no changes after heavy-ion irradiation. Significantly higher
protein level of secreted VEGF-A could be measured 72 hours after photon irradiation
in normoxic cells by ELISA analyses. Controversially discussed, I could not detect an
association between HIF-1 and SCF or Trx-1 in A549-cells in this study. Whereas
Trx-1-expression was neither influenced by changed oxygen partial pressure nor
irradiation, I could show increased SCF mRNA by quantitative Real Time-PCR and
secreted protein level by ELISA after photon irradiation independent of oxygen state.
In summary, this study showed that HIF-1 and its target genes (GLUT-1, LDHA; PDK,
VEGF) and also SCF was increased after photon irradiation and therefore could take
part in radioresistance of photon irradiation therapy in contrast to heavy ions. These
results suggest a further benefit of the radiotherapy using heavy ions for non-small cell
lung cancer.
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Dates
Created: 2013Issued: 2013-12-04Updated: 2013-12-04
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Photon Irradiation
DFG-subjects
Bestrahlung
DDC-Numbers
610
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Bill, Verena Maria (1045757799): Expression HIF-1-abhängiger Gene in humanen Lungenadenokarzinom (A549)-Zellen und deren Regulation nach Photonen- und Schwerionenbestrahlung. : Philipps-Universität Marburg 2013-12-04. DOI: https://doi.org/10.17192/z2013.0698.
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This item has been published with the following license: In Copyright