Editorial Open Access
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Sep 14, 2012; 18(34): 4629-4634
Published online Sep 14, 2012. doi: 10.3748/wjg.v18.i34.4629
MicroRNAs in inflammatory bowel disease - pathogenesis, diagnostics and therapeutics
Mehmet Coskun, Jacob Tveiten Bjerrum, Jakob Benedict Seidelin, Ole Haagen Nielsen
Mehmet Coskun, Jacob Tveiten Bjerrum, Jakob Benedict Seidelin, Ole Haagen Nielsen, Department of Gastroenterology, Medical Section 54 O3, University of Copenhagen, Herlev Hospital, DK-2730 Herlev, Denmark
Mehmet Coskun, Jacob Tveiten Bjerrum, Department of Cellular and Molecular Medicine, the Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark
Jakob Benedict Seidelin, Department of Internal Medicine I, University of Copenhagen, Bispebjerg Hospital, DK-2400 Copenhagen NV, Denmark
Author contributions: Coskun M analyzed the literature, wrote the manuscript and the final revision of the article; Bjerrum JT provided intellectual input, advice, and contributed to the writing and final revision of the manuscript; Seidelin JB and Nielsen OH contributed to the conceptual design, drafting of the manuscript and revising it critically for important intellectual content; and all authors approved the final submitted manuscript.
Supported by Grants from Fonden til Lægevidenskabens Fremme (the AP Møller Foundation); the Family Erichsen Memorial Foundation; the Lundbeck Foundation; the Axel Muusfeldts Foundation; and the Foundation of Aase and Ejnar Danielsen
Correspondence to: Mehmet Coskun, PhD, Department of Gastroenterology, Medical Section 54 O3, University of Copenhagen, Herlev Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. mehmet.coskun@regionh.dk
Telephone: +45-38-683421 Fax: +45-38-684009
Received: November 27, 2011
Revised: April 9, 2012
Accepted: April 20, 2012
Published online: September 14, 2012

Abstract

The pathogenesis of inflammatory bowel disease (IBD) is complex and largely unknown. Until recently, research has focused on the study of protein regulators in inflammation to reveal the cellular and molecular networks in the pathogenesis of IBD. However, in the last few years, new and promising insights have been generated from studies describing an association between an altered expression of a specific class of non-coding RNAs, called microRNAs (miRs or miRNAs) and IBD. The short (approximately 22 nucleotides), endogenous, single-stranded RNAs are evolutionary conserved in animals and plants, and regulate specific target mRNAs at the post-transcriptional level. MiRNAs are involved in several biological processes, including development, cell differentiation, proliferation and apoptosis. Furthermore, it is estimated that miRNAs may be responsible for regulating the expression of nearly one-third of the genes in the human genome. Thus, miRNA deregulation often results in an impaired cellular function, and a disturbance of downstream gene regulation and signaling cascades, suggesting their implication in disease etiology. Despite the identification of more than 1900 mature human miRNAs, very little is known about their biological functions and functional targets. Recent studies have identified dysregulated miRNAs in tissue samples of IBD patients and have demonstrated similar differences in circulating miRNAs in the serum of IBD patients. Thus, there is great promise that miRNAs will aid in the early diagnosis of IBD, and in the development of personalized therapies. Here, we provide a short review of the current state-of-the-art of miRNAs in IBD pathogenesis, diagnostics and therapeutics.

Key Words: Biomarker, Crohn’s disease, Diagnostics, Inflammatory bowel disease, MicroRNA, Therapeutics, Ulcerative colitis



INTRODUCTION

Inflammatory bowel disease (IBD), whose incidence is increasing[1], comprises a number of intestinal chronic relapsing inflammatory disorders[2-4], among which ulcerative colitis (UC)[5] and Crohn’s disease (CD)[6] are the two main entities. The pathogenesis of IBD remains largely unknown[7,8], but involves a complex interaction between genetic, environmental, and immunological factors[9,10]. In this context, research on microRNAs (miRs or miRNAs) is a promising new research, providing novel insights into the pathogenesis of IBD, biomarker identification, and treatment. Since their discovery and initial characterization in 1993[11,12], the number of miRNA sequences deposited in the miRBase database (Sanger Database) has grown continuously[13]. Numerous investigations have uncovered the key roles of miRNAs in several physiological networks[14-18]. Given their ability to target mRNAs and their predicted regulation of the expression of nearly one-third of all human transcripts, miRNAs have been linked to critical processes underlying development and tissue homoeostasis. Thus, dysregulation of miRNAs is implicated in the pathogenesis of several human diseases[18-26], including gastrointestinal disorders, such as cancer and inflammation[27-29]. Actually, loss of intestinal miRNAs in mouse models has been shown to impair differentiation of intestinal cells and epithelial barrier function, resulting in inflammation[30].

The discovery and role of miRNAs in IBD, particularly their role in cell signaling, seems to offer a new way of understanding this chronic disease and gives rise to new diagnostic tools and potential therapeutic strategies. Thus, it is possible that some miRNAs could serve as biomarkers for IBD, aiding early diagnosis, and lead to the development of personalized therapies.

Here we provide a short review of the current research in miRNAs in IBD; including pathogenesis, diagnostics and therapeutics.

MiRNA BIOGENESIS

MiRNAs are a recently discovered class of short (18-24 nucleotides in length), endogenous, non-coding single-stranded RNAs that regulate gene expression by controlling the stability and translation of protein-coding mRNAs[26,31,32]. A number of biological processes are regulated by miRNAs, including cell differentiation, proliferation, apoptosis, and cell cycle control[30,33,34]. Long primary miRNA transcripts (pri-miRNA) are initially transcribed by RNA polymerase II or III in the nucleus, and are then cleaved to precursor hairpin (pre-miRNA) by the microprocessor complex, Drosha and DiGeorge syndrome critical region gene 8[35-37]. Next, the pre-miRNAs are exported into the cytoplasm and further cleaved to mature miRNAs by the RNase III endonuclease, Dicer, in a complex with a trans-activator RNA binding protein[38-40]. One RNA strand from the mature miRNA is incorporated into the RNA-induced silencing complex, and guides this complex to the 3’ untranslated regions of “target” mRNA sequences, which in mammalian cells induces target mRNA degradation and suppresses protein expression[31,32,41-44].

ABBERANT EXPRESSION OF MiRNAS IN INFLAMMATORY BOWEL DISEASE

In 2008, Wu et al[45] were the first to report miRNA expression in colonic mucosa samples from IBD patients. They identified 11 miRNAs that were differentially expressed in active UC vs controls (Table 1)[45] and demonstrated an inverse relationship between macrophage inflammatory peptide-2α (previously shown to be implicated in IBD[46]) and miR-192. Similarly, Bian et al[47] found miR-150 to be significantly upregulated in inflamed colonic mucosa of UC patients, as compared to controls (Table 1), and they established an inverse correlation between miR-150 and its target, c-Myb[48], a proto-oncogene that is involved in apoptosis. Consequently, these two studies have exposed new and important insights into the pathogenesis of IBD.

Table 1 Overview of dysregulated miRNAs reported to date in tissues from inflammatory bowel disease patients.
miRNAsSample typePopulation (n)ApproachReference
miRs-192, 375, 422b, 16, 21, 23a, 24, 29a, 126, 195, and let-7fSigmoid colon biopsiesActive UC (n = 15) vs healthy controls (n = 15)Microarray and qRT-PCRWu et al[45]
miR-21 and miR-155Sigmoid colon biopsiesActive UC (n = 12) vs healthy controls (n = 12)Microarray and qRT-PCRTakagi et al[49]
miRs-19b, 629, 23b, 106a, and 191Sigmoid colon biopsiesActive CD (n = 5) vs healthy controls (n = 13)Microarray and qRT-PCRWu et al[50]
miRs-16, 21, 223, and 594Terminal ileum biopsiesActive CD (n = 6) vs healthy controls (n = 13)Microarray and qRT-PCRWu et al[50]
miRs-188-5p, 215, 320a, 346, 7, 31, 135b, 223, 29a, 29b, 126*, 127-3p, and 324-3pColon biopsiesActive UC (n = 8) vs healthy controls (n = 8)qRT-PCRFasseu et al[51]
miRs-188-5p, 215, 320a, 346, 196a, 29a, 29b, 126*, 127-3p, and 324-3pColon biopsiesInactive UC (n = 8) vs healthy controls (n = 8)qRT-PCRFasseu et al[51]
miRs-9, 126, 130a, 181c, 375, 26a, 29b, 30b, 34c-5p, 126*, 127-3p, 133b, 155, 196a, 324-3p, 21, 22, 29c, 31, 106a, 146a, 146b-3p, and 150Colon biopsiesActive CD (n = 8) vs healthy controls (n = 8)qRT-PCRFasseu et al[51]
miRs-9*, 30a*, 30c, 223, 26a, 29b, 30b, 34c-5p, 126*, 127-3p, 133b, 155, 196a, 324-3p, 21, 22, 29c, 31, 106a, 146a, 146b-3p, and 150Colon biopsiesInactive CD (n = 8) vs healthy controls (n = 8)qRT-PCRFasseu et al[51]
miRs-150, 196b, 199a-3p, 199b-5p, 223, and 320aColon biopsiesInactive UC (n = 8) vs Inactive CD (n = 8)qRT-PCRFasseu et al[51]
miR-7Colon biopsiesActive CD (n = 8) vs healthy controls (n = 6)qRT-PCRNguyen et al[53]
miR-150Colon biopsiesActive UC (n = 5) vs healthy controls (n = 4)qRT-PCRBian et al[47]
miR-196Colon biopsiesActive CD (n = 83) vs healthy controls (n = 67)qRT-PCR and ISHBrest et al[54]
miR-143 and miR-145Colon biopsiesActive UC (n = 8) vs healthy controls (n = 8)qRT-PCRPekow et al[52]

In 2010, three studies[49-51] identified altered miRNA expression in IBD tissue but without concomitant functional analyses. In a cohort of 12 controls and 12 active UC patients, Takagi et al[49] reported miR-21 and miR-155 to be significantly upregulated in inflamed colonic UC tissue (Table 1). In a second study, Wu et al[50] assayed the expression of 467 miRNAs in patients with sigmoid CD and in patients with active terminal ileal CD. They found five miRNAs to be associated with active sigmoid CD, and four miRNAs were significantly increased in active ileal CD, as compared to control tissues (Table 1)[50]. These reports were followed by a similar study by Fasseu et al[51] evaluating the expression of more than 300 miRNAs in colonic tissue samples of UC and CD patients using quantitative real-time polymerase chain reaction analysis. Several miRNAs were differentially expressed in accordance with disease type, but with a large number in common to both groups (Table 1). They identified a set of eight miRNAs (miR-26a, miR-29a, miR-29b, miR-30c, miR-126*, miR-127-3p, miR-196a, and miR-324-3p) defining quiescent IBD vs controls, and a distinct subset of 15 miRNAs that could differentiate between quiescent UC and CD (n = 16) (Table 1)[51]. These three studies illustrate the potential use of miRNAs as biomarkers and the possibilities of developing miRNA profile-based diagnostic tools.

Other recent studies have focused on certain specific miRNAs and their association with target genes. Hence, Pekow et al[52] reported an inverse correlation of the tumor suppressors miR-143 and miR-145 with their target genes, IRS-1 (miR-145), and K-RAS, API-5 and MEK-2 (miR-143). Similarly, Nguyen et al[53] demonstrated decreased levels of miR-7 in inflamed CD colonic tissue, where expression of its target, CD98, was upregulated compared with control tissue. Dysregulation of CD98 interferes with the natural proliferation and differentiation of enterocytes. These two studies[52,53] not only provided new information on the pathophysiology of the well known, but poorly understood, inflammation-driven neoplastic progress in the colonic mucosa of UC, but also provided targets for future therapeutic interventions.

Some studies have focused on single miRNAs and their relation to single-nucleotide polymorphisms (SNPs). Brest et al[54] found increased expression of miR-196 restricted to intestinal epithelial cells within inflamed CD as compared to controls. They showed that miR-196 binds to, and correlates with, a decreased expression of the immunity-related GTPase M (IRGM) protective variant (c.313C) during inflammatory conditions, but not with the IRGM c.313C>T polymorphism, IRGMT, which is strongly associated with CD in European populations[55]. In a similar study, Zwiers et al[56] found that the mutation (rs10889677 C>A) in the IL-23R gene, associated with IBD, results in loss of its binding sites for let-7e and let-7f miRNAs, leading to sustained IL-23R expression in vitro, which contribute to the chronicity of IBD. Thus, these studies indicate that single SNPs located at miRNA-binding sites are likely to affect the expression of their targets and that they might contribute to the pathogenesis of IBD.

In a semi-invasive approach and with diagnostic intentions, few studies have used whole blood instead of colonic tissue. As a proof of concept, Wu et al[57] performed a microarray-based study on whole blood from IBD patients and found a panel of differentially expressed miRNAs (Table 2) that enabled them to distinguish active IBD subtypes from each other and from controls. In a similar study by Zahm et al[58], higher concentrations of 11 miRNAs (Table 2) were found in the sera of pediatric CD patients vs controls. Receiver operating characteristic analyses resulted in a diagnostic sensitivity above 80% for CD[58]. Recently, Paraskevi et al[59] identified that 11 circulating miRNAs that were differentially expressed in blood samples from active CD vs controls, and identified a set of six miRNAs that were significantly elevated in active UC vs healthy controls (Table 2). Similarly, Duttagupta et al[60] found seven circulating miRNAs that were differentially expressed in UC patients vs controls (Table 2).

Table 2 Overview of dysregulated circulating miRNAs reported to date in sera of inflammatory bowel disease patients.
miRNAsSample typePopulation (n)ApproachReference
miRs-149*, miRplus-F1065, 199a-5p, 362-3p, 340*, 532-3p, and miRplus-E1271Peripheral bloodActive CD (n = 14) vs healthy controls (n = 13)Microarray and qRT-PCRWu et al[57]
miR-149* and miR-340*Peripheral bloodInactive CD (n = 5) vs healthy controls (n = 13)Microarray and qRT-PCRWu et al[57]
miRs-505*, 28-5p, 151-5p, 103-2*, 199a-5p, 340*, 362-3p, 532-3p, and miRplus-E1271Peripheral bloodActive UC (n = 13) vs healthy controls (n = 13)Microarray and qRT-PCRWu et al[57]
miRs-505*, 28-5p, 103-2*, 149*, 151-5p, 340*, 532-3p, and miRplus-E1153Peripheral bloodActive UC (n = 10) vs active CD (n = 14)Microarray and qRT-PCRWu et al[57]
miRs-195, 16, 93, 140, 30e, 20a, 106a, 192, 21, 484, and let-7bSerumActive CD (n = 46) vs healthy controls (n = 32)LDA qRT-PCRZahm et al[58]
miRs-16, 23a, 29a, 106a, 107, 126, 191, 199a-5p, 200c, 362-3p, and 532-3pPeripheral bloodActive CD (n = 128) vs healthy controls (n = 162)qRT-PCRParaskevi et al[59]
miRs-16, 21, 28-5p, 151-5p, 155, and 199a-5pPeripheral bloodActive UC (n = 88) vs healthy controls (n = 162)qRT-PCRParaskevi et al[59]
miRs-188-5p, 422a, 378, 500, 501-5p, 769-5p, and 874Peripheral bloodUC (n = 20) vs healthy controls (n = 20)qRT-PCRDuttagupta et al[60]

Although these studies are preliminary, they demonstrate the possibilities of developing a much-needed semi-invasive test based on differentially expressed peripheral blood miRNAs.

FUTURE USE IN DISEASE DIAGNOSTICS AND THERAPEUTICS

The studies described above have significantly increased our knowledge regarding the pathogenesis of IBD and have demonstrated the usefulness of miRNAs, not only as potential biomarkers, but also as latent targets for therapeutic interventions. However, a range of obvious challenges lie ahead, especially as identification of new miRNAs is an ongoing process. In 2008, Wu et al[45] used a miRNA microarray containing 553 known human miRNA genes, but currently more than 1900 human miRNA sequences are known[13], and new ones are identified on an almost daily basis. Consequently, this area of research is in its infancy, and future studies in the field of IBD need to focus on miRNA sequencing and using larger cohorts to address two important challenges: (1) identification of all of the miRNAs that are consistently dysregulated in IBD; and (2) to identify all of the targets of the miRNAs involved in IBD. If these challenges are met, the subsequent possibilities regarding diagnostics and therapeutics seem endless.

The potential clinical use of miRNAs is best illustrated by the most investigated and well-described miRNA, miR-21, also classified as an “oncomiR”[61,62]. The almost omnipresent overexpression of miR-21 in human cancers[62-64], including colorectal cancer, provides new options for cancer therapy[65]. Interestingly, as listed in Tables 1 and 2, miR-21 is the only miRNA commonly found to be upregulated in inflamed tissue or sera of IBD patients[45,49-51,58]. Thus, miR-21 is a potential biomarker for active IBD. It may also be of significant importance for the pathogenesis of IBD, as expression of miR-21 is mediated by nuclear factor-κB[66] - a key transcription factor involved in the pathogenesis of various human diseases, including IBD[67,68]. Unfortunately, the importance of these miRNA pathways in disease pathogenesis is unknown. Thus, functional studies are needed to address the role of miRNAs in IBD and particularly their role in cell signaling.

CONCLUSION

Currently, several clinical trials are testing the therapeutic efficacy of miRNA-based therapies; one such miRNA-target drug is “miravirsen”[69], a specific inhibitor of miR-122 that is currently in phase II clinical trials for Hepatitis C infections[70]. Within the next several years, further studies will undoubtedly provide a basis for more successful clinical trials and provide more insights in to the efficacy of miRNA-based therapeutics, including IBD.

Footnotes

Peer reviewer: Dr. Alain L Servin, French National Institute of Health and Medical Research, Inserm Unit 756, Rue Jean-Baptiste Clément, 92296 Chtenay-Malabry, France

S- Editor Gou SX L- Editor Stewart GJ E- Editor Xiong L

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References
1.  Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, Benchimol EI, Panaccione R, Ghosh S, Barkema HW. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:46-54.e42; quiz e30.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Nielsen OH, Vainer B, Rask-Madsen J. Non-IBD and noninfectious colitis. Nat Clin Pract Gastroenterol Hepatol. 2008;5:28-39.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361:2066-2078.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1689]  [Cited by in F6Publishing: 900]  [Article Influence: 129.9]  [Reference Citation Analysis (1)]
4.  Baumgart DC, Carding SR. Inflammatory bowel disease: cause and immunobiology. Lancet. 2007;369:1627-1640.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Danese S, Fiocchi C. Ulcerative colitis. N Engl J Med. 2011;365:1713-1725.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Colombel JF, Sandborn WJ, Reinisch W, Mantzaris GJ, Kornbluth A, Rachmilewitz D, Lichtiger S, D'Haens G, Diamond RH, Broussard DL. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383-1395.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1937]  [Cited by in F6Publishing: 640]  [Article Influence: 161.4]  [Reference Citation Analysis (0)]
7.  Glocker E, Grimbacher B. Inflammatory bowel disease: is it a primary immunodeficiency? Cell Mol Life Sci. 2012;69:41-48.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 66]  [Cited by in F6Publishing: 57]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
8.  Nielsen OH, Rask-Madsen J. Mediators of inflammation in chronic inflammatory bowel disease. Scand J Gastroenterol Suppl. 1996;216:149-159.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 36]  [Cited by in F6Publishing: 38]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
9.  Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature. 2011;474:298-306.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1072]  [Cited by in F6Publishing: 1030]  [Article Influence: 97.5]  [Reference Citation Analysis (0)]
10.  Tsianos EV, Katsanos KH, Tsianos VE. Role of genetics in the diagnosis and prognosis of Crohn's disease. World J Gastroenterol. 2012;18:105-118.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 33]  [Cited by in F6Publishing: 33]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
11.  Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843-854.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 7542]  [Cited by in F6Publishing: 4004]  [Article Influence: 269.4]  [Reference Citation Analysis (0)]
12.  Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans. Cell. 1993;75:855-862.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2532]  [Cited by in F6Publishing: 2417]  [Article Influence: 90.4]  [Reference Citation Analysis (0)]
13.  Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res. 2006;34:D140-D144.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2906]  [Cited by in F6Publishing: 2913]  [Article Influence: 181.6]  [Reference Citation Analysis (0)]
14.  Alvarez-Garcia I, Miska EA. MicroRNA functions in animal development and human disease. Development. 2005;132:4653-4662.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 925]  [Cited by in F6Publishing: 882]  [Article Influence: 54.4]  [Reference Citation Analysis (0)]
15.  Ventura A, Jacks T. MicroRNAs and cancer: short RNAs go a long way. Cell. 2009;136:586-591.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 636]  [Cited by in F6Publishing: 638]  [Article Influence: 48.9]  [Reference Citation Analysis (0)]
16.  Cullen BR. Viral and cellular messenger RNA targets of viral microRNAs. Nature. 2009;457:421-425.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Hagen JW, Lai EC. microRNA control of cell-cell signaling during development and disease. Cell Cycle. 2008;7:2327-2332.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Kloosterman WP, Plasterk RH. The diverse functions of microRNAs in animal development and disease. Dev Cell. 2006;11:441-450.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1435]  [Cited by in F6Publishing: 1393]  [Article Influence: 89.7]  [Reference Citation Analysis (0)]
19.  Miñones-Moyano E, Porta S, Escaramís G, Rabionet R, Iraola S, Kagerbauer B, Espinosa-Parrilla Y, Ferrer I, Estivill X, Martí E. MicroRNA profiling of Parkinson's disease brains identifies early downregulation of miR-34b/c which modulate mitochondrial function. Hum Mol Genet. 2011;20:3067-3078.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 306]  [Cited by in F6Publishing: 301]  [Article Influence: 27.8]  [Reference Citation Analysis (0)]
20.  Wang WX, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q, Rigoutsos I, Nelson PT. The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci. 2008;28:1213-1223.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 509]  [Cited by in F6Publishing: 318]  [Article Influence: 36.4]  [Reference Citation Analysis (0)]
21.  Lynn FC, Skewes-Cox P, Kosaka Y, McManus MT, Harfe BD, German MS. MicroRNA expression is required for pancreatic islet cell genesis in the mouse. Diabetes. 2007;56:2938-2945.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 260]  [Cited by in F6Publishing: 255]  [Article Influence: 17.3]  [Reference Citation Analysis (0)]
22.  Kerr TA, Korenblat KM, Davidson NO. MicroRNAs and liver disease. Transl Res. 2011;157:241-252.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 70]  [Article Influence: 6.7]  [Reference Citation Analysis (0)]
23.  Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, Doevendans PA, Mummery CL, Borlak J, Haverich A. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation. 2007;116:258-267.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 672]  [Cited by in F6Publishing: 391]  [Article Influence: 44.8]  [Reference Citation Analysis (0)]
24.  Lorenzen JM, Haller H, Thum T. MicroRNAs as mediators and therapeutic targets in chronic kidney disease. Nat Rev Nephrol. 2011;7:286-294.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Salta E, De Strooper B. Non-coding RNAs with essential roles in neurodegenerative disorders. Lancet Neurol. 2012;11:189-200.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12:861-874.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857-866.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5257]  [Cited by in F6Publishing: 5095]  [Article Influence: 350.5]  [Reference Citation Analysis (0)]
28.  Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834-838.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6629]  [Cited by in F6Publishing: 6247]  [Article Influence: 389.9]  [Reference Citation Analysis (0)]
29.  O'Connell RM, Rao DS, Baltimore D. microRNA regulation of inflammatory responses. Annu Rev Immunol. 2012;30:295-312.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 577]  [Cited by in F6Publishing: 572]  [Article Influence: 57.7]  [Reference Citation Analysis (0)]
30.  McKenna LB, Schug J, Vourekas A, McKenna JB, Bramswig NC, Friedman JR, Kaestner KH. MicroRNAs control intestinal epithelial differentiation, architecture, and barrier function. Gastroenterology. 2010;139:1654-164, 1664.e1.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 191]  [Cited by in F6Publishing: 198]  [Article Influence: 15.9]  [Reference Citation Analysis (0)]
31.  Guo H, Ingolia NT, Weissman JS, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature. 2010;466:835-840.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature. 2008;455:64-71.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Miska EA. How microRNAs control cell division, differentiation and death. Curr Opin Genet Dev. 2005;15:563-568.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 541]  [Cited by in F6Publishing: 534]  [Article Influence: 33.8]  [Reference Citation Analysis (0)]
34.  Schickel R, Boyerinas B, Park SM, Peter ME. MicroRNAs: key players in the immune system, differentiation, tumorigenesis and cell death. Oncogene. 2008;27:5959-5974.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Lee Y, Kim M, Han J, Yeom KH, Lee S, Baek SH, Kim VN. MicroRNA genes are transcribed by RNA polymerase II. EMBO J. 2004;23:4051-4060.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2648]  [Cited by in F6Publishing: 2468]  [Article Influence: 147.1]  [Reference Citation Analysis (0)]
36.  Borchert GM, Lanier W, Davidson BL. RNA polymerase III transcribes human microRNAs. Nat Struct Mol Biol. 2006;13:1097-1101.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ. Processing of primary microRNAs by the Microprocessor complex. Nature. 2004;432:231-235.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Lund E, Güttinger S, Calado A, Dahlberg JE, Kutay U. Nuclear export of microRNA precursors. Science. 2004;303:95-98.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1656]  [Cited by in F6Publishing: 1645]  [Article Influence: 92.0]  [Reference Citation Analysis (0)]
39.  Okada C, Yamashita E, Lee SJ, Shibata S, Katahira J, Nakagawa A, Yoneda Y, Tsukihara T. A high-resolution structure of the pre-microRNA nuclear export machinery. Science. 2009;326:1275-1279.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 223]  [Cited by in F6Publishing: 212]  [Article Influence: 17.2]  [Reference Citation Analysis (0)]
40.  Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003;425:415-419.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell. 2005;123:631-640.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 998]  [Cited by in F6Publishing: 944]  [Article Influence: 58.7]  [Reference Citation Analysis (0)]
42.  Selbach M, Schwanhäusser B, Thierfelder N, Fang Z, Khanin R, Rajewsky N. Widespread changes in protein synthesis induced by microRNAs. Nature. 2008;455:58-63.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP, Linsley PS, Johnson JM. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature. 2005;433:769-773.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281-297.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23450]  [Cited by in F6Publishing: 13604]  [Article Influence: 1302.8]  [Reference Citation Analysis (0)]
45.  Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, Brant SR, Chakravarti S, Kwon JH. MicroRNAs are differentially expressed in ulcerative colitis and alter expression of macrophage inflammatory peptide-2 alpha. Gastroenterology. 2008;135:1624-1635.e24.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 317]  [Cited by in F6Publishing: 352]  [Article Influence: 22.6]  [Reference Citation Analysis (0)]
46.  Wu F, Dassopoulos T, Cope L, Maitra A, Brant SR, Harris ML, Bayless TM, Parmigiani G, Chakravarti S. Genome-wide gene expression differences in Crohn's disease and ulcerative colitis from endoscopic pinch biopsies: insights into distinctive pathogenesis. Inflamm Bowel Dis. 2007;13:807-821.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 168]  [Cited by in F6Publishing: 176]  [Article Influence: 11.2]  [Reference Citation Analysis (0)]
47.  Bian Z, Li L, Cui J, Zhang H, Liu Y, Zhang CY, Zen K. Role of miR-150-targeting c-Myb in colonic epithelial disruption during dextran sulphate sodium-induced murine experimental colitis and human ulcerative colitis. J Pathol. 2011;225:544-553.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 82]  [Article Influence: 7.2]  [Reference Citation Analysis (0)]
48.  Xiao C, Calado DP, Galler G, Thai TH, Patterson HC, Wang J, Rajewsky N, Bender TP, Rajewsky K. MiR-150 controls B cell differentiation by targeting the transcription factor c-Myb. Cell. 2007;131:146-159.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 731]  [Cited by in F6Publishing: 718]  [Article Influence: 52.2]  [Reference Citation Analysis (0)]
49.  Takagi T, Naito Y, Mizushima K, Hirata I, Yagi N, Tomatsuri N, Ando T, Oyamada Y, Isozaki Y, Hongo H. Increased expression of microRNA in the inflamed colonic mucosa of patients with active ulcerative colitis. J Gastroenterol Hepatol. 2010;25 Suppl 1:S129-S133.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 126]  [Cited by in F6Publishing: 128]  [Article Influence: 10.5]  [Reference Citation Analysis (0)]
50.  Wu F, Zhang S, Dassopoulos T, Harris ML, Bayless TM, Meltzer SJ, Brant SR, Kwon JH. Identification of microRNAs associated with ileal and colonic Crohn's disease. Inflamm Bowel Dis. 2010;16:1729-1738.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 193]  [Cited by in F6Publishing: 199]  [Article Influence: 17.5]  [Reference Citation Analysis (0)]
51.  Fasseu M, Tréton X, Guichard C, Pedruzzi E, Cazals-Hatem D, Richard C, Aparicio T, Daniel F, Soulé JC, Moreau R. Identification of restricted subsets of mature microRNA abnormally expressed in inactive colonic mucosa of patients with inflammatory bowel disease. PLoS One. 2010;5:pii: e13160.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 167]  [Cited by in F6Publishing: 180]  [Article Influence: 13.9]  [Reference Citation Analysis (0)]
52.  Pekow JR, Dougherty U, Mustafi R, Zhu H, Kocherginsky M, Rubin DT, Hanauer SB, Hart J, Chang EB, Fichera A. miR-143 and miR-145 are downregulated in ulcerative colitis: putative regulators of inflammation and protooncogenes. Inflamm Bowel Dis. 2012;18:94-100.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 82]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
53.  Nguyen HT, Dalmasso G, Yan Y, Laroui H, Dahan S, Mayer L, Sitaraman SV, Merlin D. MicroRNA-7 modulates CD98 expression during intestinal epithelial cell differentiation. J Biol Chem. 2010;285:1479-1489.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 77]  [Cited by in F6Publishing: 50]  [Article Influence: 5.9]  [Reference Citation Analysis (0)]
54.  Brest P, Lapaquette P, Souidi M, Lebrigand K, Cesaro A, Vouret-Craviari V, Mari B, Barbry P, Mosnier JF, Hébuterne X. A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease. Nat Genet. 2011;43:242-245.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet. 2007;39:830-832.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Zwiers A, Kraal L, van de Pouw Kraan TC, Wurdinger T, Bouma G, Kraal G. Cutting edge: a variant of the IL-23R gene associated with inflammatory bowel disease induces loss of microRNA regulation and enhanced protein production. J Immunol. 2012;188:1573-1577.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 71]  [Article Influence: 7.4]  [Reference Citation Analysis (0)]
57.  Wu F, Guo NJ, Tian H, Marohn M, Gearhart S, Bayless TM, Brant SR, Kwon JH. Peripheral blood microRNAs distinguish active ulcerative colitis and Crohn's disease. Inflamm Bowel Dis. 2011;17:241-250.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 141]  [Cited by in F6Publishing: 141]  [Article Influence: 11.8]  [Reference Citation Analysis (0)]
58.  Zahm AM, Thayu M, Hand NJ, Horner A, Leonard MB, Friedman JR. Circulating microRNA is a biomarker of pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2011;53:26-33.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 107]  [Cited by in F6Publishing: 65]  [Article Influence: 9.7]  [Reference Citation Analysis (0)]
59.  Paraskevi A, Theodoropoulos G, Papaconstantinou I, Mantzaris G, Nikiteas N, Gazouli M. Circulating MicroRNA in inflammatory bowel disease. J Crohns Colitis. 2012;Feb 28; Epub ahead of print.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 152]  [Cited by in F6Publishing: 157]  [Article Influence: 15.2]  [Reference Citation Analysis (0)]
60.  Duttagupta R, DiRienzo S, Jiang R, Bowers J, Gollub J, Kao J, Kearney K, Rudolph D, Dawany NB, Showe MK. Genome-wide maps of circulating miRNA biomarkers for ulcerative colitis. PLoS One. 2012;7:e31241.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 65]  [Article Influence: 6.7]  [Reference Citation Analysis (1)]
61.  Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259-269.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Pan X, Wang ZX, Wang R. MicroRNA-21: a novel therapeutic target in human cancer. Cancer Biol Ther. 2011;10:1224-1232.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 232]  [Cited by in F6Publishing: 227]  [Article Influence: 19.3]  [Reference Citation Analysis (0)]
63.  Si ML, Zhu S, Wu H, Lu Z, Wu F, Mo YY. miR-21-mediated tumor growth. Oncogene. 2007;26:2799-2803.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1075]  [Cited by in F6Publishing: 1017]  [Article Influence: 67.2]  [Reference Citation Analysis (0)]
64.  Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M. MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 2005;65:7065-7070.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2769]  [Cited by in F6Publishing: 1573]  [Article Influence: 162.9]  [Reference Citation Analysis (0)]
65.  Medina PP, Nolde M, Slack FJ. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature. 2010;467:86-90.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Zhou R, Hu G, Gong AY, Chen XM. Binding of NF-kappaB p65 subunit to the promoter elements is involved in LPS-induced transactivation of miRNA genes in human biliary epithelial cells. Nucleic Acids Res. 2010;38:3222-3232.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 148]  [Cited by in F6Publishing: 146]  [Article Influence: 12.3]  [Reference Citation Analysis (0)]
67.  Pasparakis M. Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol. 2009;9:778-788.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Vallabhapurapu S, Karin M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol. 2009;27:693-733.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1706]  [Cited by in F6Publishing: 1671]  [Article Influence: 131.2]  [Reference Citation Analysis (0)]
69.  Janssen HL, Reesink HW, Zeuzem S, Lawitz E, Rodriguez-Torres M, Chen A, Davis C, King B, Levin AA, Hodges MR. A randomized, double-blind, placebo (plb) controlled safety and anti-viral proof of concept study of miravirsen (MIR), an oligonucleotide targeting miR-122, in treatment naïve patients with genotype 1 (gt1) chronic HCV infection [abstract]. Hepatology. 2011;54:1430A.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Rosen HR. Clinical practice. Chronic hepatitis C infection. N Engl J Med. 2011;364:2429-2438.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 297]  [Cited by in F6Publishing: 143]  [Article Influence: 27.0]  [Reference Citation Analysis (0)]