Der Einfluss einer Aktivierung des STAT3-Signalweges auf das Ansprechen kolorektaler Karzinomzellen auf eine Radiochemotherapie

The influence of an activation of the STAT3 pathway on the response of colorectal cancer cells on a radiochemotherapy

by Carolin Herzberg
Doctoral thesis
Date of Examination:2019-11-12
Date of issue:2019-11-04
Advisor:PD Dr. Marian Grade
Referee:PD Dr. Marian Grade
Referee:Prof. Dr. Dieter Kube
Referee:Prof. Dr. Martin Oppermann
Persistent Address: http://dx.doi.org/10.53846/goediss-7706

 

 

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Abstract

English

CRC is the third most common cancer worldwide. The standard therapy in local advanced rectal cancer is the preoperative radiochemotherapy (RCT) combined with standardized surgery. However, the heterogeneous response to the RCT requires the elucidation of the resistance-conferring factors, the establishment of molecular markers and building on this the supplementation of the RCT with targeted agents to avoid therapy failure. In prilimary work our working group could show a positive correlation between the expression of STAT3 and the resistance to RCT in colorectal cell lines. In follow-up experiments by switching-off STAT3 a better therapy response could be achieved. The present thesis treats the question if stimulating the STAT3 pathway increases the RCT resistance. For this purpose in the first part of the thesis the RCT sensible cell lines HCT116 and SW480 were transfected with siSOCS3 to switch off the endogenous inhibitor of the STAT3 pathway and thereby uninhibit STAT3 signaling. Despite using four different siRNAs targeting SOCS3 and two different methods of transfection no adequate knockdown of SOCS3 could be achieved, neither at protein nor RNA level. This partial aspect therefore was not further pursued. In the second part of the thesis the stimulation of RCT sensible cell lines with IL-6 – in a setting with and without serum starvation – increased significantly their therapy resistance depending on the time of incubation: effects could be observed in HCT116 after stimulation over night and in SW480 after stimulation for 30 min. In the third part of the thesis an ectopic overexpression of STAT3 in SW480 when associated with increased STAT3 activity enhanced the radiotherapy (RT) and RCT resistance. These results confirm the previous studies of the important role of the JAK-STAT signaling pathway in relation to RCT resistance. Subsequently, the effectiveness of anti IL-6 antibodies should be tested. In the long term inhibiting JAK-STAT signaling therapeutically combined with the standard radiochemotherapy is conceivable.
Keywords: STAT3; SOCS3; IL-6; radiochemotherapy; colorectal cancer
 
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