| dc.contributor.advisor | Grade, Marian Dr. | |
| dc.contributor.author | Kendziorra, Emil Fritz | |
| dc.date.accessioned | 2014-09-25T08:53:35Z | |
| dc.date.available | 2014-10-14T22:50:06Z | |
| dc.date.issued | 2014-09-25 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0023-98DE-1 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4678 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-4678 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
| dc.subject.ddc | 610 | de |
| dc.title | Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy | de |
| dc.type | doctoralThesis | de |
| dc.title.translated | Silencing of the Wnt transcription factor TCF4 sensitizes colorectal cancer cells to (chemo-) radiotherapy | de |
| dc.contributor.referee | Ghadimi, Michael Prof. Dr. | |
| dc.date.examination | 2014-10-07 | |
| dc.description.abstracteng | A considerable percentage of rectal cancers are resistant to standard
preoperative chemoradiotherapy. Because patients with
a priori-resistant tumors do not benefit from multimodal treatment,
understanding and overcoming this resistance remains of
utmost clinical importance. We recently reported overexpression
of the Wnt transcription factor TCF4, also known as TCF7L2, in
rectal cancers that were resistant to 5-fluorouracil-based chemoradiotherapy.
Because Wnt signaling has not been associated with
treatment response, we aimed to investigate whether TCF4 mediates
chemoradioresistance. RNA interference-mediated silencing
of TCF4 was employed in three colorectal cancer (CRC) cell lines,
and sensitivity to (chemo-) radiotherapy was assessed using a standard
colony formation assay. Silencing of TCF4 caused a significant
sensitization of CRC cells to clinically relevant doses of
X-rays. This effect was restricted to tumor cells with high T cell
factor (TCF) reporter activity, presumably in a b-catenin-independent
manner. Radiosensitization was the consequence of (i)
a transcriptional deregulation of Wnt/TCF4 target genes, (ii) a silencing-
induced G2/M phase arrest, (iii) an impaired ability to
adequately halt cell cycle progression after radiation and (iv)
a compromised DNA double strand break repair as assessed by
gH2AX staining. Taken together, our results indicate a novel
mechanism through which the Wnt transcription factor TCF4
mediates chemoradioresistance. Moreover, they suggest that
TCF4 is a promising molecular target to sensitize resistant tumor
cells to (chemo-) radiotherapy. | de |
| dc.contributor.coReferee | Binder, Claudia Prof. Dr. | |
| dc.subject.eng | TCF7L2 | de |
| dc.subject.eng | TCF4 | de |
| dc.subject.eng | Colorectal cancer | de |
| dc.subject.eng | Chemo-radiotherapy | de |
| dc.subject.eng | WNT | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0023-98DE-1-0 | |
| dc.affiliation.institute | Medizinische Fakultät | de |
| dc.subject.gokfull | PPN619875976 | de |
| dc.description.embargoed | 2014-10-14 | |
| dc.identifier.ppn | 797480455 | |