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RNA Biol. 2011 Sep-Oct; 8(5): 706–713.
Published online 2011 September 1. doi:  10.4161/rna.8.5.16154
PMCID: PMC3256347

Regulation and function of miRNA-21 in health and disease

Abstract

The small regulatory RNA microRNA-21 (miR-21) plays a crucial role in a plethora of biological functions and diseases including development, cancer, cardiovascular diseases and inflammation. The gene coding for pri-miR-21 (primary transcript containing miR-21) is located within the intronic region of the TMEM49 gene. Despite pri-miR-21 and TMEM49 are overlapping genes in the same direction of transcription, pri-miR-21 is independently transcribed by its own promoter regions and terminated with its own poly(A) tail. After transcription, primiR-21 is finally processed into mature miR-21. Expression of miR-21 has been found to be deregulated in almost all types of cancers and therefore was classified as an oncomiR. During recent years, additional roles of miR-21 in cardiovascular and pulmonary diseases, including cardiac and pulmonary fibrosis as well as myocardial infarction have been described. miR-21 additionally regulates various immunological and developmental processes. Due to the critical functions of its target proteins in various signaling pathways, miR-21 has become an attractive target for genetic and pharmacological modulation in various disease conditions.

Key words: EMT, fibrosis, gene promoter, microRNAs, miR-21

Introduction

miRNAs are a class of small non-coding RNAs whose mature products are ~22 nucleotides long. They negatively regulate gene expression by inducing translational inhibition or transcript degradation.1 Initially RNA polymerase III was described to mainly drive transcription of miRNAs. However, some primary-miRNA (pri-miRNA) transcripts are very long ranging up to several kilobases, and contain four or more uracils at a stretch, that would terminate polymerase III mediated transcription.2 MiRNA-21 was one of the first miRNAs to be identified as transcribed by RNA polymerase II, which subsequently has been identified as a major driver of miRNA transcription.

Annotation of miRNA genes has revealed that the majority of the miRNAs are intergenic. However, a significant number of miRNAs are located in sense or anti-sense strand in intronic regions.2 PrimiR-21 is one of the first human miRNA genes whose regulation was extensively studied and indeed, miR-21 is an example of an intronic miRNA. Despite that, primiR-21 has its own promoter region.3

miR-21 has been found to be upregulated in many pathological conditions including cancer and cardiovascular diseases.4 A non-transcriptional mechanism for miR-21 upregulation implying gene amplification, rather than promoter hyper-activation, has been proposed.5 However, most of the available data suggest that miR-21 expression is maintained by transcriptional and post-transcriptional regulation.3,6 Potential promoter regions of pri-miR-21 have been thoroughly studied. The actual size of pri-miR-21, the transcriptional start site (TSS) and minimal promoter region of pri-miR-21 are still subjects of debate.7

Due to its ubiquitous role in various biological processes, the interest in miRNA-21 has dramatically increased during recent years, especially in cancer and cardiovascular diseases. Several excellent reviews are already available highlighting the importance of miR-21 in cancer and cardiovascular diseases.4,7,8 Therefore, these entities are not focused in great detail in this review, but we put more emphasis on miR-21 regulation and its role in development, immunity and epithelial-to-mesenchymal transition.

Regulation of miR-21 Expression

Cullen's lab first described a miR-21 regulatory region mapping −3,403 to −2,395 upstream of the pri-miR-21.3 Three years later Loffler et al. described a very similar region mapping −3,565 to −2,415, which is inducible by IL6/Stat3.9 In a later study employing more stringent criteria, Fujita et al. described a new promoter mapping −3,770 to −3,337 upstream to the miR-21 hairpin. This has several conserved enhancer elements including binding sites for activation protein 1 (AP-1; composed of Fos and Jun family proteins), Ets/PU.1, C/EBPα, NFI, SRF, p53 and STAT3. Interestingly, the promoter region described by Fujita et al. has minimal overlap with the first described promoter in 20043 and therefore, this may suggest that these two promoter regions function independently as two separate promoters (Fig. 1). Ozsolak et al. compared transcriptional activity of different promoter regions of miR-21 and found that the promoter region described by Fujita et al. is stronger when compared to others and the first identified promoter3 is inducible in a cell line specific manner.11 More recently, Mudduluru et al. identified yet another regulatory region and two transcriptional start sites in miR-21 gene.12 In addition to positive regulators of miR-21 transcription, several transcriptional suppressors have also been reported. For example, miR-21 transcription was found to be repressed by NFI, C/EBPα.10 Dissociation of these factors from the promoter region after treatment with phorbol myristic acid (PMA) leads to enhanced promoter activity. In addition, Gfi1 13 and estrogen receptor14 were also shown to negatively regulate miR-21 promoter activity.

Figure 1
Genomic location of pri-miR-21. Gene coding for pri-miR-21 is located on chromosome 17q23.2 overlapping with a protein coding gene TMEM49. Transcriptional start sites described by Cai et al.,3 Fujita et al.10 and Mudduluru et al.12 are indicated as 1, ...

According to the standard nomenclature,15 the less abundant miRNA from each strand of a hairpin was designated with an asterisk mark. This asymmetry in the abundance is the result of asymmetric degradation of the opposing strand following Dicer processing. The strand with the less stable 5′ end has a better chance to remain undegraded.16,17 Analysis of 5′-end hairpin stability by the nearest-neighbor method for miR-21 revealed that 5′-end of miR-21* is slightly less stable than-miR-21.18 However, after Dicer mediated cleavage of 72-nt-long pre-miR-21 stem-loop to 22 nt miRNA-miRNA duplex, miR-21* is degraded and miR-21 becomes a mature miRNA.

In addition to transcriptional regulation, miR-21 expression is also regulated at the post-transcriptional level. Davis et al. showed that TGFβ and BMP4 (a member of TGFβ superfamily) upregulate pre-miR-21 expression by 4-fold within 30 min after treatment while the expression of pri-miR-21 is unaltered. They further showed that miR-21 upregulation is not affected by inhibition of RNA polymerase II by α-amanitin and a luciferase reporter construct containing the miR-21 gene promoter could not be activated by BMP4 or TGFβ treatment. In subsequent experiments, they showed that elevated miR-21 levels were due to an increase in the Drosha processing of the pri-miR-21 transcript, which is mediated by Smad proteins. After ligand stimulation, signal transducer SMADs (SMAD1/5 and SMAD2/3) were recruited to pri-miR-21 in a complex with the RNA helicase p68, a component of the Drosha microprocessor complex, which led to a fast processing of pri-miR-21 to pre-miR-21 and subsequent maturation. Interestingly, BMP6, which is also a member of the TGFβ superfamily has been shown to inhibit miR-21 expression. In breast cancer tissues an inverse correlation between BMP6 and miR-21 was observed.19 In luciferase reporter assays it has been shown that BMP6 inhibits miR-21 promoter activity through E2-box and AP1 binding sites. Similarly, BMPR1a signaling negatively regulated miR-21 expression in astrocytes, but in a post-transcriptional manner, as reduction in miR-21 levels were not accompanied by changes in pri-miR-21 levels.20 Results of these studies indicate that BMPs regulate miR-21 both positively and negatively through complex mechanisms.

Role of miR-21 in Development

After fertilization, embryos are dependent on maternally derived mRNAs for their transcriptional needs until their own transcription machinery is functional. When embryonic genome activation is initiated, maternal mRNA is degraded and miRNAs that are expressed during early developmental stages have thought to play an important role in this degradation.21 In studies employing vertebrate models of development such as zebrafish, miR-21 expression was detectable from very early stages of development. Chen et al.22 have shown that miR-21 could be detected from early developmental stages (12 h) and constituted up to 40% of all miRNAs in fibroblasts, irrespective of tissue of origin in developing zebrafish embryo. In another study involving rainbow trout (Oncorhynchus mykiss),23 it was shown that expression levels of miR-21 and Stat3, which is one of the transcription factors regulating miR-21,9 significantly increase during embryonic gene activation. They propose that miR-21 play an important role in degrading maternally inherited mRNAs by a yet unidentified mechanism.

The neuronal repressor REST (RE1-silencing transcription factor) is expressed at high levels in mouse embryonic stem (ES) cells.24 Heterozygous deletion of Rest and/or its short-interfering RNA-mediated knockdown in mouse ES cells cause a loss of self-renewal and lead to the expression of markers specific for multiple lineages.25 MiRNA expression has revealed that Rest represses this set of miRNAs including miR-21, that interfere with the expression of critical self-renewal regulators such as Oct4, Nanog and Sox2. In subsequent analyses it was found that overexpression of miR-21 by pre-miR-21, markedly decreased the self-renewing capacity of mouse ES cells by 60%. The effect of pre-miR-21 on self-renewal was specific as suppression of self-renewal by pre-miR-21 was rescued by anti-miR-21. Expression levels of the self-renewal markers Oct4, Nanog, Sox2 and c-myc were also found to be decreased in pre-miR-21-treated cells. These results suggest that miR-21, which is repressed by Rest, regulates, at least in part, the self-renewal of mouse ES cells. However, Jørgensen et al.26 and Buckley et al.27 showed that REST is not required for maintaining ESC pluripotency. Singh et al.22 reasoned that the discrepancies could be due to the differences in experimental procedures but future studies are needed to explore the exact role of miR-21 and its targets in the regulation of pluripotency.

MiR-21 has been shown to play an additional important role in branching morphogenesis28 which is a basic developmental process in the formation of many organs, such as exocrine glands, the lung or the kidney. The fetal murine submandibular salivary gland is a well analyzed model system for studying organogenesis, including branching morphogenesis. It has been shown that degradation of extracellular matrix by matrix metalloproteinases (MMPs) leads to enhancement of branching morphogenesis because extracellular matrix in the mesenchyme is remodelled during submandibular salivary gland development.29,30 Reck is a membrane-anchored inhibitor of MMPs. Therefore, inhibition of Reck results in degradation of ECM by MMPs, leading to enhancement of branching morphogenesis. At the transcriptional level, MMPs are regulated by transcriptional factors such as AP1.31,32 Incidentally PDCD4 inhibits AP1-mediated gene transactivation.33 Hayashi et al. have shown that miR-21 promotes branching morphogenesis possibly by modulating MMPs by targeting atleast RECK and PDCD4.28

Role of miR-21 in Cancer

The involvement of miRNAs in cancer emerged from several studies showing that expression of several miRNAs is deregulated in neoplastic tissues.34 The identification of several targets of miRNAs which are actually classical oncogenes or tumor suppressors has led to the widely accepted idea that miRNAs play pivotal roles in cancer initiation, progression and metastasization.35,36 miR-21 was first noted as an apoptotic suppressor in various cell lines.37 In a subsequent large scale study from 540 human samples, it was found that miR-21 is the only miRNA that is overexpressed in six solid cancers including that of lung, breast, stomach, prostate, colon and pancreas. In later studies miR-21 was established as an oncogenic miRNA and its overexpression was shown in most cancer types analysed so far.3846 Additionally, miR-21 has been proposed as a biomarker of malignancy in circulation,45,4749 sputum,50 cerebrospinal fluid51 and feces.52

Cancer is a multifactorial disease which evolves through a multistage process over a period of time driven by amassing mutations and epigenetic abnormalities in expression of multiple genes. However, despite severe disturbances in gene expression during cancer development, several studies reveal that the restoration of only one or a few of these abnormalities can profoundly inhibit the growth of cancer cells, and can lead to improvements in patient survival.5355 This apparent dependency of some cancers on one or a few genes for the maintenance of the malignant phenotype is referred as “oncogene addiction.” Medina et al. have developed a mouse model using Tet-Off and Cre-recombinase technologies to achieve tissue-specific and doxycycline-controlled expression of miR-21 under Nestin (a protein marker for neural stem cells, also expressed in adult haematopoietic cells) promoter control. The resulting NesCre8, mir-21LSL-Tetoff mice had about ten-fold upregulation of miR-21 in the brain when animals were not treated with doxycycline compared with their siblings treated with doxycycline. Results indicate that overexpression of miR-21 has led to a pre-B malignant lymphoid-like phenotype, demonstrating that miR-21 is a genuine oncogene. When miR-21 was inactivated, the tumors regressed completely with in a few days. These results demonstrate that tumors can become addicted to oncomiRs and this study emphasizes the absolute dependence of at least some cancers on miR-21 for maintenance of the malignant phenotype. Oncogene addiction of some tumors has allowed the development of targeted therapeutic modalities that profoundly benefit cancer patients.54 Similarly addiction of some cancers on miR-21 can be exploited by developing pharmacological inhibitors of miRNA miR-21. In another recent elegant study employing K-ras G12D non-small-cell lung cancer (NSCLC) mouse model, Hatley et al. have showed that incidence of lung tumors significantly high in miR-21 overexpressing mice.57 Consistent with this, deletion of miR-21 has resulted in suppression of Ras-driven transformation in vitro and tumor development in vivo.

Role of miR-21 in Immune System

In view of the mechanism of action of miRNAs, it is not surprising that miRNAs govern myriad functions in immune cells. Indeed, several recent studies have identified the importance of miRNAs in immune cell development and function.5862

During an immune response, antigen-specific naive T cells proliferate enormously and develop into effector T cells capable of executing effector functions such as cytotoxicity and cytokine secretion.63 After clearance of antigen, most of the effector T cells are eliminated by activation-induced cell death, but some antigen encountered cells differentiate into relatively quiescent T cells (memory cells), which persist over long periods of time and mount a rapid response upon re-challenge with the same antigen.64 Protein expression patterns differ enormously between effector and memory T cells.65 Wu et al. analyzed the miRNA expression profile in antigen-specific naive, effector and memory CD8 T cells and found that at least seven miRNAs are differentially expressed amongst these T-cell subsets among which six showed dramatically reduced frequencies in effector T cells compared to naive T cells, and the expression of these miRNAs tended to increase back in memory T cells. However miR-21 was an exception, showing reverse kinetics with highest frequency in effector T cells followed by memory T cells and lowest expression in naive T cells66 suggesting that miR-21 plays an important role in maintaining effector phase of the T cells.

In another study involving Sezary syndrome patients, it was observed that expression of miR-21 in neoplastic skin-homing CD4-memory T cells (Sezary cells) is higher when compared with CD4 T cells from healthy donors.67 Sezary Syndrome is characterized by constitutively activated signal transducer and activator of transcription 3 (STAT3). In this study, van der Fits et al. showed that miR-21 is a direct STAT3 target in Sezary cells. Further, stimulation of Sezary cells or healthy CD4 T cells with IL-21 results in a strong activation of STAT3, and subsequent upregulation of miR-21 expression suggesting a casual relationship between STAT3 and miR-21 67 and a more general role of miR-21 in STAT3 mediated immune functions.

Asthma is a chronic inflammatory disease characterized by inflammation of the airways, tissue remodeling and decreased respiratory function. MiRNAs may play an important role in asthma as it is characterized by marked changes in gene and protein expression in the lung.68,69 By using three different experimental animal models of asthma viz, OVA (ovalbumin), Aspergillus fumigatus, lung specific-IL-13 overexpression, Lu et al.70 have shown that IL-12p35 (a component of IL-12) expression is downregulated during asthma, which is correlated with increased expression of miR-21. Subsequent analyses have shown that miR-21 was primarily detected in the cytoplasm of mononuclear and multinucleated myeloid cells and its expression significantly increases in asthma. Target validation experiments show that IL-12p35 is a target of miR-21. IL-12 is a key cytokine derived from macrophages and dendritic cells and is involved in adaptive immune responses involving Th1 cell polarization, suggesting that in addition to asthma, miR-21 may play an important role in regulation of Th1 immune responses in general. However, this needs to be validated in further models of inflammation and infection.

miRNA expression analysis of monocytes from children with allergic rhinitis has indicated that miR-21 is one of the miRNAs that were most significantly downregulated in allergic rhinitis and this decrease in miR-21 expression is coupled with enhanced miR-21-target gene TGFβ receptor 2 (TGFBR2).71 However, it is not known whether targeting of TGFBR2 by miR-21 has any functional consequence in allergic rhinitis. None the less, the study reiterates that miR-21 may have a role in immune cell functions.

Lipopolysaccharide (LPS) is a membrane glycolipid of Gram-negative bacteria and recognition of LPS by the innate immune system can lead to uncontrollable cytokine production, which can result in cardiovascular collapse and hemodynamic instability, and can eventually cause fatal sepsis syndrome in humans. In humans, exposure to LPS increases severity of chronic obstructive pulmonary disease.72 Many negative regulatory mechanisms exist to counter the toxic effects of LPS. These include soluble decoy receptors, such as Toll-like receptor 4 (TLR4) and signal transduction proteins such as MyD88-S, IRAK-M and TAG.73 The inhibitor of transcription factor NFκB α-subunit (IκBα) is promptly resynthesized by NFκB in an autoregulatory way to block excessive transcription factor activity after treatment with LPS.74 PDCD4 is one of the transcriptional targets of NFκB, and it is expression is inducible by cytokine treatment.33 PDCD4 suppresses expression of IL-10 and IL-4 in an eLF4 dependent manner75 and PDCD4-deficient mice are resistant to models of inflammatory disease, such as experimental autoimmune encephalomyelitis and streptozotocin-induced type II diabetes. Therefore, by virtue of its ability to suppress IL-10 translation, PDCD4 is believed to function as a pro-inflammatory protein.76 Consistent with this, Sheedy et al. have shown that PDCD4 deficient mice were protected from LPS-induced death. In subsequent experiments they found that treatment of human peripheral blood mononuclear cells with LPS resulted in lower PDCD4 expression which was associated with enhanced miR-21 expression. Further they showed that expression of miR-21 was mediated directly by MyD88 and NFκB. These results are particularly interesting as they offer an opportunity to modulate TLR4 activity therapeutically by regulating miR-21 expression, which may have implications in the use of TLR4 in vaccine adjutancy77 or in inflammatory diseases such as sepsis, rheumatoid arthritis and allergic asthma.

Role of miR-21 in Epithelial-to-Mesenchymal Transition and Fibrosis

Adult fibroblasts are considered to be derived directly from embryonic mesenchymal cells78 and increase in number as a result of the proliferation.79 However, recent evidence from various models of organ fibrosis suggests that fibroblasts may also be derived from epithelial or endothelial cells via a process called epithelial-to-mesenchymal-transition (or endothelial-to-mesenchymal transition for endothelial cells).8087 TGFβ is the most potent inducer of EMT or EndMT and it is the primary cytokine driving fibrosis in various organs.8890 Signaling molecules, such as AKT (Protein kinase B),91,92 integrin linked kinase,93 RhoA and beta-catenin have been implicated in TGFβ induced EMT. Importantly, as discussed in previous sections, miR-21 is rapidly inducible after TGFβ treatment,6,94 suggesting that it may play an important role in TGFβ induced pro-fibrotic effects, possibly via initiating or fostering EMT or EndMT. PTEN which is a validated target of miR-21 95,96 is a negative regulator of epithelial-to-mesenchymal transition.97,98 PTEN also negatively regulates Akt/PKB activation, which has been implicated in EMT99104 as well as in EndMT.85,105 Consistent with this, expression of PTEN is effectively suppressed by TGFβ (and hence it is also called TEP1; TGFβ-regulated and epithelial cell-enriched phosphatase).106 All these observations suggest that miR-21 may play an important role in EMT or EndMT. Indeed, recent studies19,94 have confirmed the role of miR-21 in EMT, suggesting its crucial role in organ fibrosis.

More direct evidence for the role of miR-21 in organ fibrosis comes from the studies in mouse models of cardiac107 and pulmonary fibrosis.108 Thum et al. have shown that miRNA-21 is weakly expressed in normal myocardium where as its expression is elevated in failing myocardium.109 Further analysis revealed that miR-21 is overexpressed predominantly in cardiac fibroblasts, expression being highest in fibroblasts from the failing heart.96,107 Apoptotic response induced by miR-21 inhibition in cardiac fibroblasts is sensitive to ERK-MAPK signaling and overexpression of miR-21 led to a significant increase in ERK-MAP kinase activation suggesting that miR-21 is a mediator of ERK-MAPK signaling, which is crucial for fibroblast survival and activation, which also plays an important role in many cancers.110 Target validation experiments revealed that Sprouty1, a negative regulator of ERK-MAPK signaling, is a target of miR-21. Injection of chemically modified antisense oligonucleotides specific for miR-21 (antagomiR-21) into mice subjected to pressure overload of the left ventricle by transverse aortic constriction (TAC), normalized changes in SPRY1 expression, MAP kinase activation and reduced fibrosis.107

The role of miR-21 in organ fibrosis and the anti-fibrotic action of miR-21 inhibitors were further confirmed by a later study in bleomycin induced pulmonary fibrosis model.108 Results of this study indicate that miR-21 is highly upregulated in the lungs of mice with bleomycin-induced lung fibrosis and in the lungs of patients with idiopathic pulmonary fibrosis. miR-21 is primarily enriched in myofibroblasts in the fibrotic lungs. Likewise increased miR-21 expression in colorectal cancer tissue was mainly found in fibroblasts surrounding the cancer cells.111 As mentioned in the previous sections, the authors found that miR-21 is upregulated by TGFβ which in turn inhibited Smad7 (inhibitory Smad) leading to amplification of TGFβ signaling finally resulting in a fibrotic response in human primary fibroblasts. Sequestration of miR-21 in mouse lungs effectively attenuated bleomycin induced fibrosis suggesting a central role for miR-21 the pathogenesis of lung fibrosis. Interestingly, the chemical nature of the oligonucleotides used for miR-21 inhibition in vivo, may affect the therapeutic benefit. For example, Patrick et al.112 studied the role of miR-21 in pathological cardiac remodelling by injecting miR-21 inhibitors in mice exposed to transverse aortic constriction (TAC) for six weeks. Consistent with previous reports in reference 107 and 113 they observed enhanced cardiac miR-21 expression after TAC. However, they used short (8-nt) oligonucleotides against miR-21, which were different to the long oligonucleotide (22-nt) used by Thum et al.107,114 and failed to block the remodeling response of the heart to stress. In addition, the authors observed that miR-21, null mice still displayed cardiac hypertrophy and fibrosis in response to cardiac stress, which may be explainable by genetic compensatory mechanisms over the course of development.

Conclusion

The increasing information about the role of miR-21 (409 hits for “miR-21” keyword in PubMed as on 09-03-2011) suggests that miR-21 plays a very crucial role in many biological processes. Despite considerable development in understanding the transcriptional regulation of miR-21, precise mechanisms driving its upregulation are not completely understood. As discussed in previous sections, the miR-21 promoter regions have binding sites for several transcriptional factors such as AP1, STAT3, SRF, etc., but not all target genes of those factors (for example eNOS for AP1,115 miR-1 for SRF) 116 show upregulation as miR-21 in pathological conditions like heart failure. Although it could be explainable by post-transcriptional regulation of mature miR-21 expression,6 further studies are needed to ascertain the underlying mechanisms, which may offer additional level of control for pharmacological modulation of miR-21 for therapeutic reasons. Although, inhibition of miR-21 has been shown to provide significant benefit during cancer or heart failure in mice models,56,57,107 similar studies in larger animal models and other disease conditions are clearly needed to ascertain the therapeutic gain after miR-21 modulation.

Abbreviations

AP1
activator protein 1
EMT
epithelial-to-mesenchymal transition
miR-21
microRNA21
NFI
nuclear factor I
STAT3
signal transducer and activator of transcription 3
TSS
transcriptional start site

Note

This work was supported by the BMBF (# 01EO0802 to TT) and the Deutsche Forschungsgemeinschaft (DFG TH903/10-1 to TT).

References

1. Ambros V, Lee RC, Lavanway A, Williams PT, Jewell D. MicroRNAs and other tiny endogenous RNAs in C. elegans. Curr Biol. 2003;13:807–818. [PubMed]
2. Kim VN. MicroRNA biogenesis: Coordinated cropping and dicing. Nat Rev Mol Cell Biol. 2005;6:376–385. [PubMed]
3. Cai X, Hagedorn CH, Cullen BR. Human micro-RNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs. RNA. 2004;10:1957–1966. [PubMed]
4. Jazbutyte V, Thum T. MicroRNA-21: From cancer to cardiovascular disease. Curr Drug Targets. 2010;11:926–935. [PubMed]
5. Haverty PM, Fridlyand J, Li L, Getz G, Beroukhim R, Lohr S, et al. High-resolution genomic and expression analyses of copy number alterations in breast tumors. Genes Chromosomes Cancer. 2008;47:530–542. [PubMed]
6. Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008;454:56–61. [PMC free article] [PubMed]
7. Ribas J, Lupold SE. The transcriptional regulation of miR-21, its multiple transcripts, and their implication in prostate cancer. Cell Cycle. 2010;9:923–929. [PMC free article] [PubMed]
8. Selcuklu SD, Donoghue MT, Spillane C. miR-21 as a key regulator of oncogenic processes. Biochem Soc Trans. 2009;37:918–925. [PubMed]
9. Loffler D, Brocke-Heidrich K, Pfeifer G, Stocsits C, Hackermuller J, Kretzschmar AK, et al. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood. 2007;110:1330–1333. [PubMed]
10. Fujita S, Ito T, Mizutani T, Minoguchi S, Yamamichi N, Sakurai K, Iba H. miR-21 gene expression triggered by AP-1 is sustained through a double-negative feedback mechanism. J Mol Biol. 2008;378:492–504. [PubMed]
11. Ozsolak F, Poling LL, Wang Z, Liu H, Liu XS, Roeder RG, et al. Chromatin structure analyses identify miRNA promoters. Genes Dev. 2008;22:3172–3183. [PubMed]
12. Mudduluru G, George-William JN, Muppala S, Asangani IA, Kumarswamy R, Nelson LD, Allgayer H. Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Biosci Rep. 2011;31:185–197. [PubMed]
13. Velu CS, Baktula AM, Grimes HL. Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood. 2009;113:4720–4728. [PubMed]
14. Wickramasinghe NS, Manavalan TT, Dougherty SM, Riggs KA, Li Y, Klinge CM. Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells. Nucleic Acids Res. 2009;37:2584–2595. [PMC free article] [PubMed]
15. Ambros V, Bartel B, Bartel DP, Burge CB, Carrington JC, Chen X, et al. A uniform system for microRNA annotation. RNA. 2003;9:277–279. [PubMed]
16. Khvorova A, Reynolds A, Jayasena SD. Functional siRNAs and miRNAs exhibit strand bias. Cell. 2003;115:209–216. [PubMed]
17. Schwarz DS, Hutvagner G, Du T, Xu Z, Aronin N, Zamore PD. Asymmetry in the assembly of the RNAi enzyme complex. Cell. 2003;115:199–208. [PubMed]
18. Coutinho LL, Matukumalli LK, Sonstegard TS, Van Tassell CP, Gasbarre LC, Capuco AV, Smith TP. Discovery and profiling of bovine microRNAs from immune-related and embryonic tissues. Physiol Genomics. 2007;29:35–43. [PubMed]
19. Du J, Yang S, An D, Hu F, Yuan W, Zhai C, Zhu T. BMP-6 inhibits microRNA-21 expression in breast cancer through repressing deltaEF1 and AP-1. Cell Res. 2009;19:487–496. [PubMed]
20. Sahni V, Mukhopadhyay A, Tysseling V, Hebert A, Birch D, Mcguire TL, et al. BMPR1a and BMPR1b signaling exert opposing effects on gliosis after spinal cord injury. J Neurosci. 2010;30:1839–1855. [PMC free article] [PubMed]
21. Schier AF. The maternal-zygotic transition: Death and birth of RNAs. Science. 2007;316:406–407. [PubMed]
22. Chen PY, Manninga H, Slanchev K, Chien M, Russo JJ, Ju J, et al. The developmental miRNA profiles of zebrafish as determined by small RNA cloning. Genes Dev. 2005;19:1288–1293. [PubMed]
23. Ramachandra RK, Salem M, Gahr S, Rexroad CE, 3rd, Yao J. Cloning and characterization of microRNAs from rainbow trout (oncorhynchus mykiss): Their expression during early embryonic development. BMC Dev Biol. 2008;8:41. [PMC free article] [PubMed]
24. Ballas N, Grunseich C, Lu DD, Speh JC, Mandel G. REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis. Cell. 2005;121:645–657. [PubMed]
25. Singh SK, Kagalwala MN, Parker-Thornburg J, Adams H, Majumder S. REST maintains self-renewal and pluripotency of embryonic stem cells. Nature. 2008;453:223–227. [PMC free article] [PubMed]
26. Jorgensen HF, Chen ZF, Merkenschlager M, Fisher AG. Is REST required for ESC pluripotency? Nature. 2009;457:4–5. [PubMed]
27. Buckley NJ, Johnson R, Sun YM, Stanton LW. Is REST a regulator of pluripotency? Nature. 2009;457:5–6. [PubMed]
28. Hayashi T, Koyama N, Azuma Y, Kashimata M. Mesenchymal miR-21 regulates branching morphogenesis in murine submandibular gland in vitro. Dev Biol. 2011;352:299–307. [PubMed]
29. Umeda Y, Miyazaki Y, Shiinoki H, Higashiyama S, Nakanishi Y, Hieda Y. Involvement of heparin-binding EGF-like growth factor and its processing by metalloproteinases in early epithelial morphogenesis of the submandibular gland. Dev Biol. 2001;237:202–211. [PubMed]
30. Hotary K, Allen E, Punturieri A, Yana I, Weiss SJ. Regulation of cell invasion and morphogenesis in a three-dimensional type I collagen matrix by membrane-type matrix metalloproteinases 1, 2 and 3. J Cell Biol. 2000;149:1309–1323. [PMC free article] [PubMed]
31. Angel P, Imagawa M, Chiu R, Stein B, Imbra RJ, Rahmsdorf HJ, et al. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor. Cell. 1987;49:729–739. [PubMed]
32. Benbow U, Brinckerhoff CE. The AP-1 site and MMP gene regulation: What is all the fuss about? Matrix Biol. 1997;15:519–526. [PubMed]
33. Yang HS, Jansen AP, Nair R, Shibahara K, Verma AK, Cmarik JL, Colburn NH. A novel transformation suppressor, Pdcd4, inhibits AP-1 transactivation but not NFkappaB or ODC transactivation. Oncogene. 2001;20:669–676. [PubMed]
34. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–838. [PubMed]
35. Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–269. [PubMed]
36. Zhang W, Dahlberg JE, Tam W. MicroRNAs in tumor-igenesis: A primer. Am J Pathol. 2007;171:728–738. [PubMed]
37. Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65:6029–6033. [PubMed]
38. Asangani IA, Rasheed SA, Nikolova DA, Leupold JH, Colburn NH, Post S, Allgayer H. MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer. Oncogene. 2008;27:2128–2136. [PubMed]
39. Frankel LB, Christoffersen NR, Jacobsen A, Lindow M, Krogh A, Lund AH. Programmed cell death 4 (PDCD4) is an important functional target of the microRNA miR-21 in breast cancer cells. J Biol Chem. 2008;283:1026–1033. [PubMed]
40. Li T, Li D, Sha J, Sun P, Huang Y. MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochem Biophys Res Commun. 2009;383:280–285. [PubMed]
41. Lu Z, Liu M, Stribinskis V, Klinge CM, Ramos KS, Colburn NH, Li Y. MicroRNA-21 promotes cell transformation by targeting the programmed cell death 4 gene. Oncogene. 2008;27:4373–4379. [PubMed]
42. Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1) J Biol Chem. 2007;282:14328–14336. [PubMed]
43. Zhu S, Wu H, Wu F, Nie D, Sheng S, Mo YY. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Res. 2008;18:350–359. [PubMed]
44. Zheng J, Xue H, Wang T, Jiang Y, Liu B, Li J, et al. miR-21 downregulates the tumor suppressor P12(CDK2AP1) and stimulates cell proliferation and invasion. J Cell Biochem. 2011;112:872–880. [PubMed]
45. Xu J, Wu C, Che X, Wang L, Yu D, Zhang T, et al. Circulating microRNAs, miR-21, miR-122 and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Mol Carcinog. 2011;50:136–142. [PubMed]
46. Schramedei K, Morbt N, Pfeifer G, Lauter J, Rosolowski M, Tomm JM, et al. MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4. Oncogene. 2011;30:2975–2985. [PMC free article] [PubMed]
47. Alisi A, Da Sacco L, Bruscalupi G, Piemonte F, Panera N, De Vito R, et al. Mirnome analysis reveals novel molecular determinants in the pathogenesis of diet-induced nonalcoholic fatty liver disease. Lab Invest. 2011;91:283–293. [PubMed]
48. Asaga S, Kuo C, Nguyen T, Terpenning M, Giuliano AE, Hoon DS. Direct serum assay for microRNA-21 concentrations in early and advanced breast cancer. Clin Chem. 2011;57:84–91. [PubMed]
49. 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;102:1174–1179. [PMC free article] [PubMed]
50. Yu L, Todd NW, Xing L, Xie Y, Zhang H, Liu Z, et al. Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers. Int J Cancer. 2010;127:2870–2878. [PMC free article] [PubMed]
51. Baraniskin A, Kuhnhenn J, Schlegel U, Chan A, Deckert M, Gold R, et al. Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central nervous system. Blood. 2011;117:3140–3146. [PubMed]
52. Link A, Balaguer F, Shen Y, Nagasaka T, Lozano JJ, Boland CR, Goel A. Fecal MicroRNAs as novel biomarkers for colon cancer screening. Cancer Epidemiol Biomarkers Prev. 2010;19:1766–1774. [PMC free article] [PubMed]
53. Weinstein IB. Cancer. addiction to oncogenes—the achilles heal of cancer. Science. 2002;297:63–64. [PubMed]
54. Weinstein IB, Joe AK. Mechanisms of disease: Oncogene addiction—a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol. 2006;3:448–457. [PubMed]
55. Weinstein IB, Joe A. Oncogene addiction. Cancer Res. 2008;68:3077–3080. [PubMed]
56. 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]
57. Hatley ME, Patrick DM, Garcia MR, Richardson JA, Bassel-Duby R, van Rooij E, Olson EN. Modulation of K-ras-dependent lung tumorigenesis by MicroRNA-21. Cancer Cell. 2010;18:282–293. [PMC free article] [PubMed]
58. Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83–86. [PubMed]
59. Zhou B, Wang S, Mayr C, Bartel DP, Lodish HF. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc Natl Acad Sci USA. 2007;104:7080–7085. [PubMed]
60. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316:604–608. [PubMed]
61. Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316:608–611. [PMC free article] [PubMed]
62. Manjunath N, Shankar P, Wan J, Weninger W, Crowley MA, Hieshima K, et al. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J Clin Invest. 2001;108:871–878. [PMC free article] [PubMed]
63. Butz EA, Bevan MJ. Massive expansion of antigen-specific CD8+ T cells during an acute virus infection. Immunity. 1998;8:167–175. [PMC free article] [PubMed]
64. Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: Implications for vaccine development. Nat Rev Immunol. 2002;2:251–262. [PubMed]
65. Kaech SM, Hemby S, Kersh E, Ahmed R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell. 2002;111:837–851. [PubMed]
66. Wu H, Neilson JR, Kumar P, Manocha M, Shankar P, Sharp PA, Manjunath N. miRNA profiling of naive, effector and memory CD8 T cells. PLoS One. 2007;2:1020. [PMC free article] [PubMed]
67. van der Fits L, van Kester MS, Qin Y, Out-Luiting JJ, Smit F, Zoutman WH, et al. MicroRNA-21 expression in CD4+ T cells is regulated by STAT3 and is pathologically involved in sezary syndrome. J Invest Dermatol. 2011;131:762–768. [PubMed]
68. Lewis CC, Yang JY, Huang X, Banerjee SK, Blackburn MR, Baluk P, et al. Disease-specific gene expression profiling in multiple models of lung disease. Am J Respir Crit Care Med. 2008;177:376–387. [PMC free article] [PubMed]
69. Kuperman DA, Lewis CC, Woodruff PG, Rodriguez MW, Yang YH, Dolganov GM, et al. Dissecting asthma using focused transgenic modeling and functional genomics. J Allergy Clin Immunol. 2005;116:305–311. [PubMed]
70. Lu TX, Munitz A, Rothenberg ME. MicroRNA-21 is upregulated in allergic airway inflammation and regulates IL-12p35 expression. J Immunol. 2009;182:4994–5002. [PubMed]
71. Chen RF, Huang HC, Ou CY, Hsu TY, Chuang H, Chang JC, et al. MicroRNA-21 expression in neonatal blood associated with antenatal immunoglobulin E production and development of allergic rhinitis. Clin Exp Allergy. 2010;40:1482–1490. [PubMed]
72. Triantafilou M, Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol. 2002;23:301–304. [PubMed]
73. Liew FY, Xu D, Brint EK, O'Neill LA. Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol. 2005;5:446–458. [PubMed]
74. Sun SC, Ganchi PA, Ballard DW, Greene WC. NFkappaB controls expression of inhibitor I kappa B alpha: Evidence for an inducible autoregulatory pathway. Science. 1993;259:1912–1915. [PubMed]
75. Hilliard A, Hilliard B, Zheng SJ, Sun H, Miwa T, Song W, Goke R, Chen YH. Translational regulation of autoimmune inflammation and lymphoma genesis by programmed cell death 4. J Immunol. 2006;177:8095–8102. [PubMed]
76. Sheedy FJ, Palsson-McDermott E, Hennessy EJ, Martin C, O'Leary JJ, Ruan Q, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol. 2010;11:141–147. [PubMed]
77. van Duin D, Medzhitov R, Shaw AC. Triggering TLR signaling in vaccination. Trends Immunol. 2006;27:49–55. [PubMed]
78. Lang H, Fekete DM. Lineage analysis in the chicken inner ear shows differences in clonal dispersion for epithelial, neuronal and mesenchymal cells. Dev Biol. 2001;234:120–137. [PubMed]
79. Weber KT. Monitoring tissue repair and fibrosis from a distance. Circulation. 1997;96:2488–2492. [PubMed]
80. Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R. Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol. 2008;19:2282–2287. [PubMed]
81. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 2007;67:10123–10128. [PubMed]
82. Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007;13:952–961. [PubMed]
83. Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem. 2007;282:23337–23347. [PubMed]
84. Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003;112:1776–1784. [PMC free article] [PubMed]
85. Widyantoro B, Emoto N, Nakayama K, Anggrahini DW, Adiarto S, Iwasa N, et al. Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition. Circulation. 2010;121:2407–2418. [PubMed]
86. Hashimoto N, Phan SH, Imaizumi K, Matsuo M, Nakashima H, Kawabe T, et al. Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol. 2010;43:161–172. [PMC free article] [PubMed]
87. Chapman HA. Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol. 2011;73:413–435. [PubMed]
88. Sheppard D. Transforming growth factor beta: A central modulator of pulmonary and airway inflammation and fibrosis. Proc Am Thorac Soc. 2006;3:413–417. [PMC free article] [PubMed]
89. Sime PJ, Xing Z, Graham FL, Csaky KG, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta1 induces prolonged severe fibrosis in rat lung. J Clin Invest. 1997;100:768–776. [PMC free article] [PubMed]
90. Vallance BA, Gunawan MI, Hewlett B, Bercik P, Van Kampen C, Galeazzi F, et al. TGFbeta1 gene transfer to the mouse colon leads to intestinal fibrosis. Am J Physiol Gastrointest Liver Physiol. 2005;289:116–128. [PubMed]
91. Kattla JJ, Carew RM, Heljic M, Godson C, Brazil DP. Protein kinase B/Akt activity is involved in renal TGFbeta1-driven epithelial-mesenchymal transition in vitro and in vivo. Am J Physiol Renal Physiol. 2008;295:215–225. [PMC free article] [PubMed]
92. Hubchak SC, Sparks EE, Hayashida T, Schnaper HW. Rac1 promotes TGFbeta-stimulated mesangial cell type I collagen expression through a PI3K/Akt-dependent mechanism. Am J Physiol Renal Physiol. 2009;297:1316–1323. [PubMed]
93. Li Y, Yang J, Dai C, Wu C, Liu Y. Role for integrin-linked kinase in mediating tubular epithelial to mesenchymal transition and renal interstitial fibrogenesis. J Clin Invest. 2003;112:503–516. [PMC free article] [PubMed]
94. Cottonham CL, Kaneko S, Xu L. miR-21 and miR-31 converge on TIAM1 to regulate migration and invasion of colon carcinoma cells. J Biol Chem. 2010;285:35293–35302. [PubMed]
95. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133:647–658. [PubMed]
96. Roy S, Khanna S, Hussain SR, Biswas S, Azad A, Rink C, et al. MicroRNA expression in response to murine myocardial infarction: MiR-21 regulates fibroblast metalloprotease-2 via phosphatase and tensin homologue. Cardiovasc Res. 2009;82:21–29. [PMC free article] [PubMed]
97. Song LB, Li J, Liao WT, Feng Y, Yu CP, Hu LJ, et al. The polycomb group protein bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. J Clin Invest. 2009;119:3626–3636. [PMC free article] [PubMed]
98. Wang H, Quah SY, Dong JM, Manser E, Tang JP, Zeng Q. PRL-3 downregulates PTEN expression and signals through PI3K to promote epithelial-mesenchymal transition. Cancer Res. 2007;67:2922–2926. [PubMed]
99. Bakin AV, Tomlinson AK, Bhowmick NA, Moses HL, Arteaga CL. Phosphatidylinositol-3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migration. J Biol Chem. 2000;275:36803–36810. [PubMed]
100. Grille SJ, Bellacosa A, Upson J, Klein-Szanto AJ, van Roy F, Lee-Kwon W, et al. The protein kinase akt induces epithelial mesenchymal transition and promotes enhanced motility and invasiveness of squamous cell carcinoma lines. Cancer Res. 2003;63:2172–2178. [PubMed]
101. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: Role of phosphatidylinositol-3′-kinase/AKT pathways. Oncogene. 2005;24:7443–7454. [PubMed]
102. Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, et al. Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol. 2005;171:1023–1034. [PMC free article] [PubMed]
103. Julien S, Puig I, Caretti E, Bonaventure J, Nelles L, van Roy F, et al. Activation of NFkappaB by akt upregulates snail expression and induces epithelium mesenchyme transition. Oncogene. 2007;26:7445–7456. [PubMed]
104. Yan W, Fu Y, Tian D, Liao J, Liu M, Wang B, et al. PI3 kinase/Akt signaling mediates epithelial-mesenchymal transition in hypoxic hepatocellular carcinoma cells. Biochem Biophys Res Commun. 2009;382:631–636. [PubMed]
105. Meadows KN, Iyer S, Stevens MV, Wang D, Shechter S, Perruzzi C, et al. Akt promotes endocardial-mesenchyme transition. J Angiogenes Res. 2009;1:2. [PMC free article] [PubMed]
106. Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res. 1997;57:2124–2129. [PubMed]
107. Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature. 2008;456:980–984. [PubMed]
108. Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med. 2010;207:1589–1597. [PMC free article] [PubMed]
109. Thum T, Galuppo P, Wolf C, Fiedler J, Kneitz S, van Laake LW, et al. MicroRNAs in the human heart: A clue to fetal gene reprogramming in heart failure. Circulation. 2007;116:258–267. [PubMed]
110. Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802:396–405. [PubMed]
111. Nielsen BS, Jorgensen S, Fog JU, Sokilde R, Christensen IJ, Hansen U, et al. High levels of microRNA-21 in the stroma of colorectal cancers predict short disease-free survival in stage II colon cancer patients. Clin Exp Metastasis. 2011;28:27–38. [PMC free article] [PubMed]
112. Patrick DM, Montgomery RL, Qi X, Obad S, Kauppinen S, Hill JA, et al. Stress-dependent cardiac remodeling occurs in the absence of microRNA-21 in mice. J Clin Invest. 2010;120:3912–3916. [PMC free article] [PubMed]
113. Sayed D, Rane S, Lypowy J, He M, Chen IY, Vashistha H, et al. MicroRNA-21 targets Sprouty2 and promotes cellular outgrowths. Mol Biol Cell. 2008;19:3272–3282. [PMC free article] [PubMed]
114. Thum T, Chau N, Bhat B, Gupta SK, Linsley PS, Bauersachs J, Engelhardt S. Comparison of different miR-21 inhibitor chemistries in a cardiac disease model. J Clin Invest. 2011;121:461–462. [PMC free article] [PubMed]
115. Xing F, Jiang Y, Liu J, Zhao K, Mo Y, Qin Q, et al. Role of AP1 element in the activation of human eNOS promoter by lysophosphatidylcholine. J Cell Biochem. 2006;98:872–884. [PubMed]
116. Chen JF, Mandel EM, Thomson JM, Wu Q, Callis TE, Hammond SM, et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet. 2006;38:228–233. [PMC free article] [PubMed]

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