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Differences in the expression of microRNAs implicated in colorectal carcinogenesis and involved in the WNT signalling pathway in the macroscopically-normal epithelium of people at higher-risk of colorectal cancer

Published online by Cambridge University Press:  15 April 2015

F. C. Malcomson
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
N. D. Willis
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
I. McCallum
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
L. Xie
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
S. Kelly
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
M. Bradburn
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
N. J. Belshaw
Affiliation:
Institute of Food Research, Norwich Research Park, Norfolk NR4 7UA, UK
I. T. Johnson
Affiliation:
Institute of Food Research, Norwich Research Park, Norfolk NR4 7UA, UK
J. C. Mathers
Affiliation:
Human Nutrition Research Centre, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne NE4 5PL, UK
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Abstract

Type
Abstract
Copyright
Copyright © The Authors 2015 

People with ulcerative colitis (UC) or adenomatous polyps (adenomas) are at increased risk of colorectal cancer (CRC)(Reference Itzkowitz and Yio1). Altered expression of microRNAs (miRNAs), small non-coding RNAs that regulate gene expression post-transcriptionally, has been observed in those with UC(Reference Coskun, Bjerrum and Seidelin2) and adenomas(Reference Oberg, French and Sarver3). Importantly, abnormally-expressed miRNAs contribute to the initiation and progression of CRC and are potential biomarkers for diagnosis and prognosis of this cancer(Reference Schetter, Okayama and Harris4). This study aimed to investigate differences in the expression of a panel of miRNAs in the macroscopically-normal mucosa of people at higher-risk of CRC.

We quantified expression of 8 miRNAs that are (i) implicated in CRC, (ii) regulators of WNT signalling, a pathway frequently aberrantly activated in CRC(Reference Bienz and Clevers5), and/or (iii) whose expression is altered by butyrate treatment in healthy participants (n = 56) and in patients at higher CRC risk with quiescent UC (n = 26) or history of adenomatous polyps (n = 12). RNA was isolated from mucosal biopsies of macroscopically-normal tissue collected at 10 cm from the anal verge. cDNA was synthesised by reverse transcription and used to quantify the expression of miR-17, miR-19a, miR-19b, miR-20a, miR-25, miR-93, miR-106b and miR-424 by quantitative PCR. For normally distributed data, the ANOVA General Linear Model was used to compare miRNA expression between the 3 risk groups, adjusting for age, sex and endoscopy procedure as covariates. Where data were not normally distributed, the non-parametric Kruskal-Wallis test was used.

We observed significantly higher miR-424 expression (p < 0·01), a miRNA reported to be increased in CRCs(Reference Wang, Zhang and Zhang6), and reduced miR-20a expression (p = 0·055) in participants with quiescent UC (Table 1). miR-20a expression also appears to be reduced in polyp patients. Alterations in miRNA expression may be detected in the healthy tissue of people at higher-risk of CRC and may represent very early molecular changes contributing to the progression from normal mucosa to carcinoma.

Table 1. Median and range values for miRNA expression expressed as adjusted copies (2−ΔCt × 1,000) relative to the geometric mean of RNU6 and SNORD68 controls.

** p < 0·01 and *p < 0·1 for differences between risk groups (Kruskal-Wallis test).

This study was funded by the BBSRC (BB/H005013/1). Ethical approval for the study was granted on 10th December 2009 (REC No. 09/H0907/77).

References

1.Itzkowitz, SH & Yio, X (2004) Am J Physiol Gastrointest Liver Physiol 287, G717.Google Scholar
2.Coskun, M, Bjerrum, JT, Seidelin, JB (2012) World J Gastroenterol 18, 46294634.Google Scholar
3.Oberg, AL, French, AJ, Sarver, AL et al. (2011) PLoS One 6, e20465.Google Scholar
4.Schetter, AJ, Okayama, H, Harris, CC (2012) Cancer J 18, 244252.Google Scholar
5.Bienz, M & Clevers, H (2000) Cell 103, 311320.Google Scholar
6.Wang, YX, Zhang, XY, Zhang, BF et al. (2013) J Dig Dis 11, 5054.Google Scholar
Figure 0

Table 1. Median and range values for miRNA expression expressed as adjusted copies (2−ΔCt × 1,000) relative to the geometric mean of RNU6 and SNORD68 controls.