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Title: The role of physical activity in the molecular regulation of colon cancer risk
Author: Shaw, Barnabas
ISNI:       0000 0004 5990 2922
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2015
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A strong body of observational evidence supports the notion that physical activity (PA) is inversely associated with colon cancer (CC) risk. Epigenetic alterations, such as aberrant DNA methylation, are apparent in the early stages of carcinogenesis. Recent evidence has suggested that PA can alter DNA methylation patterns in a variety of tissues. It is not known whether PA can affect DNA methylation patterns in genes implicated in CC risk. Study 1 was a longitudinal investigation of 253 females (70.7 ± 4.0 yrs) and 137 males (71.4 ± 4.3 yrs) for whom DNA from peripheral blood leukocytes were available. Participants showed differential DNA methylation of relevant genes depending on whether they had increased, decreased, or maintained their PA level over eight years. Study 2 was a randomised controlled trial of sedentary colon adenoma patients (n = 31; 68.5 ± 3.2 yrs) who were randomised to a 6-12 month Active Lifestyle Programme or Usual Care. DNA methylation patterns of CC risk genes in buccal cells were unaffected by taking part in the Active Lifestyle Programme. Low recruitment probably resulted in the study being underpowered, and buccal cells may not have been a suitable surrogate marker of colon DNA methylation. A lack of colon biopsies prevented any analysis of changes in methylation in this tissue. Due to the absence of colon biopsies, Study 3 tested whether serum from physically active or inactive volunteers affected the proliferation of in vitro models of colon epithelia, in the fasted state and after a single bout of treadmill running. A randomised controlled trial with a crossover design was conducted in 20 male participants (59 ± 6.0 yrs) free of metabolic or cardiovascular disease, and data pooled together with 20 male colon adenoma patients from the previous investigation. This study showed that male adenoma patients’ cardiorespiratory fitness was inversely correlated with serum-stimulated growth of the colorectal cancer cell line Caco-2 in vitro, but no relationship was observed in disease-free volunteers at rest or after exercise. In conclusion, this series of studies demonstrated that whilst PA is associated with beneficial changes in DNA methylation longitudinally, this might not be realised in a trial setting with sedentary older persons. It remains unclear whether increasing PA is an effective strategy for reducing CC risk via changes to DNA methylation patterns. Furthermore, it has suggested that cardiorespiratory fitness might be important in modulating the growth of the Caco-2 cell line, but more investigation is needed.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available