Aim: This study aimed to investigate whether plasma miR-21 and miR-92a levels may be used to differentiate between patients with irritable bowel syndrome (IBS), ulcerative colitis (UC), and colorectal cancer (CRC).
Background: miRNA expression profiles are well characterized in CRC, but these expression profiles in UC and IBS remain promising. Screening of high-risk individuals for these diseases has substantial clinical benefits.
Methods: This was a case-control study. We quantified plasma miR-21 and miR-92a expression levels in 100 samples (37 with active UC, 33 with CRC, and 30 with IBS as well as 30 healthy controls) using real-time PCR. Their diagnostic performance for discriminating these diseases was assessed using receiver-operation characteristic curve (AUC-ROC).
Results: The studied miRNAs were differentially expressed among all participated groups. Plasma miR-21 and miR-92a levels exhibited significant upregulation in CRC as compared to IBS, UC, and healthy subjects. Both miRNAs were upregulated in the UC group as compared to IBS and healthy subjects. ROC analysis revealed promising diagnostic performance for miR-21 and miR-92a in discriminating UC from non-UC groups (IBS and healthy subjects) with AUCs of 0.844 and 0.979 respectively. It also distinguished between CRC and UC with AUCs of 0.968 and 0.887 respectively and with reasonable sensitivities and specificities.
Conclusion: Circulating miR-21 and miR-92a can be exploited not only as potential noninvasive biomarkers for detection of CRC, but also for differentiation between functional and organic colorectal disorders.
Keywords: miR-21, miR-92a, Colorectal cancer, Irritable bowel syndrome, Ulcerative colitis.
(Please cite as: Ahmed Hassan E, El-Din Abd El-Rehim AS, Mohammed Kholef EF, Abd-Elgwad Elsewify W. Potential role of plasma miR-21 and miR-92a in distinguishing between irritable bowel syndrome, ulcerative colitis, and colorectal cancer. Gastroenterol Hepatol Bed Bench 2020;13(2):147-154).
Zhen Y, Luo C, Zhang H. Early detection of ulcerative colitis-associated colorectal cancer. Gastroenterol Rep 2018;6:83-92.
Xavier RJ, Podolsky DK. Unraveling the pathogenesis of inﬂammatory bowel disease. Nature 2007;448:427-34.
Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inﬂammatory bowel disease. Nature 2011;474:298-306.
Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut 2001;48:526-35.
Breynaert C, Vermeire S, Rutgeerts P, Van Assche G. Dysplasia and colorectal cancer in inflammatory bowel disease: a result of inflammation or an intrinsic risk? Acta Gastroenterol Belg 2008;71:367-72.
Kavanagh DO, Carter MC, Keegan D, Doherty G, Smith MJ, Hyland JM, et al. Management of colorectal cancer in patients with inflammatory bowel disease. Tech Coloproctol 2014;18:23-8.
Jess T, Rungoe C, Peyrin-Biroulet L. Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies. Clin Gastroenterol Hepatol 2012;10:639-45.
Jess T, Simonsen J, Jorgensen KT, Pedersen BV, Nielsen NM, Frisch M. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. Gastroenterology 2012;143:375-81.
Beaugerie L, Svrcek M, Seksik P, Bouvier AM, Simon T, Allez M, et al. Risk of colorectal high grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology 2013;145:166-75.
Dugum M, Lin J, Lopez R, Estfan B, Manilich E, Stocchi L, et al. Recurrence and survival rates of inflammatory bowel disease-associated colorectal cancer following postoperative chemotherapy: a comparative study. Gastroenterol Rep 2017;5:57-61.
Wang J, Zhang KY, Liu SM, Sen S. Tumor-associated circulating micrornas as biomarkers of cancer. Molecules 2014;19:1912-38.
Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005;120:15-20.
Iborra M, Bernuzzi F, Invernizzi P, Danese S. MicroRNAs in autoimmunity and inflammatory bowel disease: crucial regulators in immune response. Autoimmun Rev 2012;11:305-14.
Wu WK, Law PT, Lee CW, Cho CH, Fan D, Wu K, et al. MicroRNA in colorectal cancer: from benchtop to bedside. Carcinogenesis 2011;32:247-53.
Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature 2011;474:307-17.
Wu F, Guo NJ, Tian H, Marohn M, Gearhart S, Bayless TM, et al. Peripheral blood microRNAs distinguish active ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis 2011;17:241-50.
Paraskevi A, Theodoropoulos G, Papaconstantinou I, Mantzaris G, Nikiteas N, Gazouli M. Circulating microRNA in inflammatory bowel disease. J Crohns Colitis 2012;6:900-4.
Ng EK, Chong WW, Jin H, Lam EK, Shin VY, Yu J, et al. Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut 2009;58:1375-81.
Tsujiura M, Ichikawa D, Komatsu S, Shiozaki A, Takeshita H, Kosuga T, et al. Circulating microRNAs in plasma of patients with gastric cancers. Br J Cancer 2010;102:1174-9.
Kaiser T, Langhorst J, Wittkowski H, Becker K, Friedrich AW, Rueffer A, et al. Faecal S100A12 as a non-invasive marker distinguishing inflammatory bowel disease from irritable bowel syndrome. Gut 2007;56:1706-13.
Takagi T, Naito Y, Mizushima K, Hirata I, Yagi N, Tomatsuri N, et al. Increased expression of microRNA in the inﬂamed colonic mucosa of patients with active ulcerative colitis. J Gastroenterol Hepatol 2010;25:129-33.
Yang Y, Ma Y, Shi C, Chen H, Zhang H, Chen N, et al. Overexpression of miR-21 in patients with ulcerative colitis impairs intestinal epithelial barrier function through targeting the Rho GTPase RhoB. Biochem Biophys Res Commun 2013;434:746-52.
Ordas I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Ulcerative colitis. Lancet 2012;380:1606-19.
Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317(26):1625-9.
Drossman DA, Hasler WL. Rome IV-functional GI disorders: disorders of gut-brain interaction. Gastroenterology 2016;150:1257-61.
Sobin L, Wittekind C, Editors. TNM classification of malignant tumors. New York: Wiley-Liss; 2002.
Jiang S, Li C, Olive V, Lykken E, Feng F, Sevilla J, et al. Molecular dissection of the miR-17-92 cluster’s critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation. Blood 2011;118:5487-97.
Wu F, Dong F, Arendovich N, Zhang J, Huang Y, Kwon JH. Divergent influence of microRNA-21 deletion on murine colitis phenotypes. Inflamm Bowel Dis 2014;20:1972-85.
Yang G, Yang L, Wang W, Wang J, Wang J, Xu Z. Discovery and validation of extracellular/circulating microRNAs during idiopathic pulmonary fibrosis disease progression. Gene 2015;562:138-44.
Ludwig K, Fassan M, Mescoli C, Pizzi M, Balistreri M, Albertoni L, et al. PDCD4/miR-21 dysregulation in inﬂammatory bowel disease-associated carcinogenesis. Virchows Arch 2013;462:57-63.
Spiller RC. Role of infection in irritable bowel syndrome. J Gastroenterol 2007;42:41-7.
Zhou Q, Zhang B, Verne GN. Intestinal membrane permeability and hyper-sensitivity in the irritable bowel syndrome. Pain 2009;146:41-6.
Zhou Q, Souba WW, Croce C, Verne GN. MicroRNA-29a regulates intestinal membrane permeability in patients with irritable bowel syndrome. Gut 2010;59:775-84.
Kapeller J, Houghton LA, Mönnikes H, Walstab J, Möller D, Bönisch H, et al. First evidence for an association of a functional variant in the microRNA-510 target site of the serotonin receptor-type 3E gene with diarrhea predominant irritable bowel syndrome. Hum Mol Genet 2008;17:2967-77.
Ahmed FE, Jeffries CD, Vos PW, Flake G, Nuovo GJ, Sinar DR, et al. Diagnostic microRNA markers for screening sporadic human colon cancer and active ulcerative colitis in stool and tissue. Cancer Genomics Proteomics 2009;6:281-95.
Wang B, Zhang Q. The expression and clinical significance of circulating microRNA-21 in serum of five solid tumors. J Cancer Res Clin Oncol 2012;138:1659-66.
Tsuchida A, Ohno S, Wu W, Borjigin N, Fujita K., Aoki T, et al. miR-92 is a key oncogenic component of the miR-17-92 cluster in colon cancer. Cancer Sci 2011;102:2264-71.
Humphreys KJ, Cobiac L, Le Leu RK, Van der Hoek MB, Michael MZ. Histone deacetylase inhibition in colorectal cancer cells reveals competing roles for members of the oncogenic miR-17-92 cluster. Mol Carcinog 2013;52:459-74.
Bickeboller M, Tagscherer KE, Kloor M, Jansen L, Chang Claude J, Brenner H, et al. Functional characterization of the tumor-suppressor MARCKS in colorectal cancer and its association with survival. Oncogene 2015;34:1150-9.
Sveen A, Agesen TH, Nesbakken A, Rognum TO, Lothe RA, Skotheim RI. Transcriptome instability in colorectal cancer identified by exon microarray analyses: Associations with splicing factor expression levels and patient survival. Genome Med 2011;3:32.
Balaguer F, Moreira L, Lozano JJ, Link A, Ramirez G, Shen Y, et al. Colorectal cancers with microsatellite instability display unique miRNA profiles. Clin Cancer Res 2011;17:6239-49.