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

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 Award	19 Mar 2019
Original language	English
Awarding Institution	University of Bristol
Supervisor	Ann C Williams (Supervisor) & Keith W Brown (Supervisor)