Investigating the effect of circadian rhythm regulator Bmal1 on tumorigenesis in APCmin/- mice
Type of Proposal
Oral Presentation
Faculty
Faculty of Science
Faculty Sponsor
Phillip Karpowicz
Proposal
Colorectal cancer is the second most commonly diagnosed cancer in Canada and among top three leading causes of cancer deaths. The rate of colorectal cancer is especially increased when the familial adenomatous polyposis coli (APC) gene is mutated. The APCmin/- mouse, which carries a heterozygous mutation of the Apc gene, is therefore a valuable model for studying colorectal cancer. The circadian rhythm contributes to a host of physiological activities in mammals, including sleep-wake cycle and immune response. It also plays an important role in numerous cellular processes, such as cell proliferation and differentiation. On a molecular level, the ‘rhythm’ is maintained by various negative feedback loops, leading to oscillating transcript and protein levels of several core clock genes, such as BMAL1, CLOCK, CRY 1-2 and PER 1-3. Recent studies show that dysfunction of circadian rhythm is strongly implicated in colorectal cancer. Abnormal levels of clock gene transcripts are found in more aggressive tumours and associated with worse disease prognosis. However, the precise mechanisms by which clock genes affect tumorigenesis are unclear. To investigate this correlation, we used Apcmin/-Bmal1-/- and Apcmin/-Bmal1+/+ mice and synchronized their clock activity, marked as time point 0 (ZT0). We then subjected the mice to a 12-hour light/12-hour dark rhythm, and collected intestinal samples at ZT4 and ZT12. Both genotypes of mice had significant polyp formations, as predicted given the Apc mutation. However, the Apcmin/-Bmal1-/- mice had twice as many tumours than the controls. This increase in tumorigenesis can be seen throughout the small intestine. There are many potential explanations for this result, including increase in cell proliferation, decrease in apoptosis, and dysregulation of cell differentiation. We are currently using cell staining methods to look for markers of these cellular activities to further understand the role of BMAL in tumorigenesis.
Start Date
23-3-2018 10:35 AM
End Date
23-3-2018 11:55 AM
Location
Alumni Auditorium B
Investigating the effect of circadian rhythm regulator Bmal1 on tumorigenesis in APCmin/- mice
Alumni Auditorium B
Colorectal cancer is the second most commonly diagnosed cancer in Canada and among top three leading causes of cancer deaths. The rate of colorectal cancer is especially increased when the familial adenomatous polyposis coli (APC) gene is mutated. The APCmin/- mouse, which carries a heterozygous mutation of the Apc gene, is therefore a valuable model for studying colorectal cancer. The circadian rhythm contributes to a host of physiological activities in mammals, including sleep-wake cycle and immune response. It also plays an important role in numerous cellular processes, such as cell proliferation and differentiation. On a molecular level, the ‘rhythm’ is maintained by various negative feedback loops, leading to oscillating transcript and protein levels of several core clock genes, such as BMAL1, CLOCK, CRY 1-2 and PER 1-3. Recent studies show that dysfunction of circadian rhythm is strongly implicated in colorectal cancer. Abnormal levels of clock gene transcripts are found in more aggressive tumours and associated with worse disease prognosis. However, the precise mechanisms by which clock genes affect tumorigenesis are unclear. To investigate this correlation, we used Apcmin/-Bmal1-/- and Apcmin/-Bmal1+/+ mice and synchronized their clock activity, marked as time point 0 (ZT0). We then subjected the mice to a 12-hour light/12-hour dark rhythm, and collected intestinal samples at ZT4 and ZT12. Both genotypes of mice had significant polyp formations, as predicted given the Apc mutation. However, the Apcmin/-Bmal1-/- mice had twice as many tumours than the controls. This increase in tumorigenesis can be seen throughout the small intestine. There are many potential explanations for this result, including increase in cell proliferation, decrease in apoptosis, and dysregulation of cell differentiation. We are currently using cell staining methods to look for markers of these cellular activities to further understand the role of BMAL in tumorigenesis.