The role of BCL-3 in apoptosis and therapy response in rectal cancer

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Colorectal cancer (CRC) is a major cause of cancer related mortality and is the second most common cause of cancer deaths in the UK (CRUK). Despite year on year improvements in survival, the five-year survival for all patients remains less than 60%. For locally advanced rectal cancer (LARC), surgical resection is a mainstay of management, alongside pre-operative long-course chemoradiotherapy (LCCRT). Tumour regression grade (TRG) in LARC is variable and patient’s tumours that fail to regress with radiation have much poorer prognosis. Understanding why patients have a poor TRG is critical to improving survival from rectal cancer.
The proto-oncogene BCL-3 is upregulated in a subset of CRCs. BCL-3 expression predicts patient prognosis in advanced disease and has been shown to protect colon cancer cells from apoptosis. However, little is known regarding the role of BCL-3 in rectal cancer, specifically, concerning BCL-3’s role in promoting tumour cell survival or in the response to irradiation.
Results reveal that BCL-3 is expressed rectal cancer cells. BCL-3 suppression was shown to increase expression of the pro-apoptotic BH3-only BCL-2 family member Bim, leading to apoptosis. BCL-3 and p52 were identified at κB consensus sites on the BCL2L11 promoter. Moreover, BCL-3 suppression increased acetylated histone 3 abundance at the BCL2L11 promoter, suggesting BCL-3 loss, results in transcriptional activation of Bim. Additionally, BCL-3 protects rectal cancer cells from -irradiation and loss results in exacerbated and prolonged H2AX foci formation.
These data suggest that BCL-3 plays an important role in the DNA damage response of CRC cells. Interestingly, immunohistochemistry of rectal cancer biopsies showed that BCL-3 expression may predict TRG to LCCRT. Excitingly, these data suggest a dual action for anti-BCL-3 therapeutics: targeting BCL-3 may be important for prevention and/or treatment, causing tumour cell death, whereas inhibiting BCL-3 function, in the subset of patients with increased BCL-3 expression in tumours, may increase the response to LCCRT and drive improvements in prognosis for these patients.
Date of Award19 Mar 2019
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorAnn C Williams (Supervisor) & Keith W Brown (Supervisor)

Keywords

  • rectal cancer
  • chemoradiation
  • apoptosis
  • therapy response

Cite this

'