Exploring the role of BCL-3 in colorectal cancer cell therapeutic resistance

  • Chris T Parker

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Despite continuing improvements in the management of colorectal cancer (CRC), the disease remains the second most common cause of cancer mortality in the UK. Around 30% of colorectal tumours are located in the rectum making them more challenging to remove surgically. In locally advanced cases of rectal cancer, chemoradiotherapy is given alongside surgery to improve overall outcome. A significant proportion of patients do not respond to chemoradiotherapy however and identifying the reasons for this will improve their management. BCL-3 isa proto-oncogene, upregulated ina subset of colorectal tumours, correlating with lower patient survival. Previous work identified a role for BCL-3 as a survival factor in colorectal cancer but little is known about the role of BCL-3 in response to the DNA damaging agents used in chemoradiotherapy. This work therefore set out to determine whether BCL-3 expression could help tumours resist therapy.Results presented here demonstrate that loss of BCL-3 in CRC cells sensitises them to ionising radiation, increasing persistence of DNA double strand breaks (DSBs) after treatment. Reporter assays and drug treatmentsshowed that loss of BCL-3 reduced the efficiency of homologous recombination (HR), a major pathway for DSB repair. To better understand the role of BCL-3 in HR, BCL-3 was deleted in a CRC cell line by CRISPR-Cas9 genome editing, allowing the importance of BCL-3 expression to be studied in 3D cell culture. BCL-3 knockout cells were used in phosphoproteomics to gain insight into the mechanism of the role of BCL-3 in HR. Results suggest that loss of BCL-3 may be reducing the chromatin remodelling required for HR, identifying a novel function of BCL-3 in colorectal cancer. Importantly, this work provides rationale for targeting BCL-3 to improve response to chemoradiotherapy as well as for the use of BCL-3 as a predictive marker for the effectiveness of this treatment.
Date of Award24 Jun 2021
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorPaul B Martin (Supervisor), Pete J Cullen (Supervisor) & Ann C Williams (Supervisor)

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