The role of physical activity in the molecular regulation of colon cancer risk

Shaw, Barnabas (2015) The role of physical activity in the molecular regulation of colon cancer risk. Doctoral thesis, University of East Anglia.

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Abstract

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.

Item Type:	Thesis (Doctoral)
Faculty \ School:	Faculty of Medicine and Health Sciences > School of Health Sciences
Depositing User:	Jackie Webb
Date Deposited:	07 Dec 2016 09:43
Last Modified:	07 Dec 2016 09:43
URI:	https://ueaeprints.uea.ac.uk/id/eprint/61635
DOI:

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