Date of Award
Circadian Clock, Colorectal Cancer, Inflammation, Intestine, Tumourigenesis
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The circadian clock is an endogenous cycle that temporally coordinates physiological and behavioural processes with the Earth’s rotation about its axis. This molecular clock has been proposed to control multiple fundamental biological processes such as metabolism, cell cycle and proliferation-processes in which abnormalities have been shown to be tumourigenic. Epidemiological studies suggest shift workers are at an increased risk for various cancers including breast and colorectal cancer. Colorectal cancer is initiated by mutations to the Adenomatous Polyposis Coli (APC) gene in which loss of heterozygosity results in constitutive Wnt signaling, resulting in increased cellular proliferation. Previous work done in the lab has shown that APCmin/+ mice that lack all circadian behavioural and physiological rhythms due to a mutation in the core, non-redundent clock gene, BMAL1, produce two times the number of intestinal tumours. I hypothesized that that the BMAL1-/-¬-dependent increase in tumourigenesis was due to an intrinsic intestinal epithelial mechanism. To test this, immunohistochemistry was used to characterize 3 mechanisms of intestinal biology: 1. circadian clock status, 2. cell production and Wnt signalling and 3. inflammation. This data revealed that clock mutant animals exhibit a slight decrease in intestinal turnover suggesting an abnormality in tissue homeostasis. The role the intestinal clock specifically plays in tumourigenesis was investigated using a conditional knockout of BMAL1 in only the intestinal epithelium. The conditional knock out mice exhibited increased tumour initiation; however, tumour growth and progression were unaffected. Additionally, prolonged inflammation further increased tumour initiation events in both wild type and conditional knock out animals but is not implicated in BMAL1-/- induced tumour growth. Together, these data suggest the intrinsic intestinal circadian clock supresses tumour initiation.
Trombley, Chantelle, "The Effect of BMAL1 on Intestinal Tumourigenesis" (2020). Electronic Theses and Dissertations. 8486.