Die Rolle von CBP bei der Strahlenresistenzentwicklung im kolorektalen Karzinom
The Role of CBP in Radiation Resistance Development in Colorectal Carcinoma
von Cornelius Franz Menze
Datum der mündl. Prüfung:2019-08-15
Erschienen:2019-07-22
Betreuer:PD Dr. Sebastian Dango
Gutachter:Prof. Dr. Michael Ghadimi
Gutachter:Prof. Dr. Björn Chapuy
Gutachter:Prof. Dr. Matthias Dobbelstein
Dateien
Name:CM_Promotion_2019-07-15.pdf
Size:848.Kb
Format:PDF
Zusammenfassung
Englisch
This thesis focuses on the protein CBP (CREB-binding protein) in colorectal cancer. CBP is a histone acetyltransferase with 4 transactivation domains and acetylates a wide variety of proteins. CBP is a multifunctional protein that affects a multitude of pro-proliferative oncogenic and pro-apoptotic anti-proliferative signal transduction cascades, also in tumors. The aim of thesis was to analyse the presumed CBP-mediated modulation of tumour proliferation and the possible influence on the development of resistance using the example of rectal cancer. First, we used immunohistochemical methods to determine whether and to what extent CBP expression in tumors is related to clinical parameters in patients with rectal cancer. We found that high CBP expression in tumors has a positive effect on patient survival. 5-year survival is over 30% lower for patients with low CBP expression in the tumor than for patients with moderate to high CBP expression. In addition, a positive influence of increased CBP expression on the recurrence behavior of tumors can be observed at least in the tendency. As a second step, molecular biological aspects of a CBP knockdown were examined for tumor proliferation using CBP-relevant signal cascades. On the cell biological level we were able to demonstrate that CBP is a vital protein for the organism and that a complete knockdown has a lethal effect. We were showed that CBP, although very dynamic, is involved in the regulation of some signaling molecules that are important for tumor proliferation. A complete knockout of CBP also has an effect on the expression of interaction partners. A knockout of the oncogenic proteins c-myc, c-jun and ß-catenin was observed. In addition, we analysed the biologically functional role of CBP in the development of resistances and were demonstrated that suppression tends to lead to sensitisation towards radiation- and chemotherapy in rectal cancer. Looking at these results in their entirety, it becomes clear that the protein CBP represents a central switching point in the organism and can play an important role in tumor cell proliferation. The consequences of dysregulation of CBP expression can be manifold. However, further functional tests are needed to assess the actual role of this versatile protein in the development and progression of malignant diseases.
Keywords: CBP; cancer; colorectal cancer