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Cell Cycle. Author manuscript; available in PMC 2009 August 15. Published in final edited form as: Published online 2008 August 17. | PMCID: PMC2654364 NIHMSID: NIHMS92599 |
Functional integration of microRNAs into oncogenic and tumor suppressor pathways Craig D. Lotterman, Oliver A. Kent, and Joshua T. Mendell* McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205 A large body of evidence has documented abnormal microRNA (miRNA) expression patterns in diverse human malignancies. Given that miRNA expression is tightly regulated during development and cellular differentiation, aberrant miRNA expression in cancer cells is likely to be in part a consequence of the loss of normal cellular identity that accompanies malignant transformation. Nevertheless, it is now clear that miRNAs function as critical effectors of several canonical oncogenic and tumor suppressor pathways, including those controlled by Myc and p53. Gain- and loss-of-function of these factors in cancer cells contributes to miRNA dysregulation, directly influencing neoplastic phenotypes including cellular proliferation and apoptosis. Keywords: MicroRNA, Oncogene, Tumor suppressor, c-Myc, p53, Nuclear factor-κB, Fusion oncoprotein, Gene expression Initially discovered as developmental regulators in C. elegans in the early 1990's, 1 microRNAs (miRNAs) are now recognized as core components of a fundamental mechanism of gene regulation in multicellular eukaryotes that broadly influences gene expression. miRNAs are small noncoding RNAs, ~18-24 nucleotides in length, that regulate the translation or stability of target mRNAs. miRNAs are first transcribed by RNA polymerase II as long primary transcripts (pri-miRNAs) that undergo a series of endonucleolytic cleavages to produce the mature miRNA species. Fully processed miRNAs are incorporated into a protein complex known as the RNA-induced silencing complex (RISC) and recognize sites of imperfect complementarity in 3′ untranslated regions (UTRs) of target messages. It is now appreciated that miRNA regulation impacts widespread developmental and cellular processes. Early in the study of miRNAs it became clear that these molecules were likely to play a significant role in cancer pathogenesis. In both C. elegans and Drosophila, miRNAs were linked to fundamental cellular processes related to oncogenesis including differentiation, proliferation, and apoptosis. A direct link between miRNAs and cancer came first from studies of chronic lymhphocytic leukemia (CLL). Calin et al. recognized that a pair of miRNAs, miR-15a and miR-16-1, are located in a minimal region of chromosome 13q14 that is deleted in over half of CLL cases. 2 They additionally showed that these miRNAs are downregulated in over two-thirds of CLL cases. The significance of reduced function of these miRNAs was further highlighted when it was discovered that they target BCL2, an anti-apoptotic oncogene that is often overexpressed in CLL. 3 Since these observations, the evidence that miRNAs play a causative role in tumorigenesis has been accumulating rapidly. For example, specific miRNAs are known to be targets of genetic lesions that activate oncogenes and inactivate tumor suppressors in cancer cells such as deletion, amplification, chromosomal rearrangements, and methylation. 4, 5 Moreover, several miRNAs have been experimentally demonstrated to possess oncogenic or tumor suppressor activity. These include the pro-tumorigenic miR-17-92 cluster, miR-155, miR-21, and miR-372/373 as well as the anti-tumorigenic let-7 family. 6-10 More broadly, profiling studies have documented widespread dysregulation of miRNAs in virtually all examined tumor types. These studies have revealed that miRNA expression patterns are highly informative for cancer diagnosis, prognosis, and response to therapy. 11-16Several mechanisms likely contribute to the extensive dysregulation of miRNAs that has been observed in cancer cells. Since miRNA expression is tightly regulated during programs of cellular differentiation, the incomplete or abnormal differentiation status of many cancer cells likely affects the expression levels of many miRNAs. Superimposed on such expression changes, however, one might expect miRNAs that are directly controlled by oncogenic and tumor suppressor pathways to also exhibit abnormal expression patterns. Indeed, there is growing evidence that miRNAs are critical components of several canonical signaling pathways that frequently undergo gain- and loss-of-function in cancer including those controlled by Myc, p53, and NF-κB. In this review, we discuss how miRNAs have been integrated into oncogenic and tumor suppressor pathways and how these functions illuminate our understanding of the roles of miRNAs in tumorigenesis. miRNAs in Oncogenic Pathways Myc-regulated miRNAs c-MYC (referred to hereafter as MYC) encodes a helix-loop-helix transcription factor and is one of the most frequently activated proto-oncogenes in human cancers. Through the activation and repression of a diverse set of target genes, Myc activity potently drives cellular proliferation and tumorigenesis. In addition to directly controlling the expression of many protein-coding genes, there is a growing appreciation that the ability of Myc to reprogram miRNA expression also contributes significantly to its oncogenic activity (). Indeed, the first demonstration that an oncogene directly controls miRNA expression was provided by O'Donnell et al. who showed that the miR-17-92 cluster is directly transactivated by Myc. 17 The miR-17-92 cluster encodes 6 miRNAs (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, and miR-92-1) which are grouped within a highly conserved 800 base-pair region of human chromosome 13q31.3, a region known to be frequently amplified in both hematopoietic as well as solid malignancies. 18 Chromatin immunoprecipitation (ChIP) demonstrates that Myc interacts directly with a conserved binding site within the first intron of C13orf25, the miR-17-92 primary transcript, activating its transcription. Widespread overexpression of these miRNAs has been observed in human malignancies perhaps reflecting the frequent hyperactivity of Myc in cancer. 19 Recently, the MYCN oncogene, which is structurally and functionally related to MYC and is commonly amplified in neuroblastoma, was also demonstrated to induce expression of the miR-17-92 cluster. 20 Several lines of evidence indicate that induction of this miRNA cluster contributes to the pro-oncogenic effects of Myc activity. For example, ectopic expression of these miRNAs in the Eμ- Myc transgenic mouse model of B cell lymphoma dramatically accelerates disease onset and aggressiveness. 21 These affects appear to be due primarily to the ability of these miRNAs to inhibit apoptosis of lymphoma cells which normally occurs at high frequency in Eμ- Myc animals. Similarly, enforced expression of miR-17-92 in the B and T cell lineage of mice leads to a lymphoproliferative disease and autoimmunity. 22 In a solid tumor model, the miR-17-92 cluster is able to promote angiogenesis and thereby promote tumor growth in a non-cell autonomous fashion. 23 Numerous downstream targets of the miR-17-92 cluster have been characterized which begin to illuminate the oncogenic mechanisms mediated by these miRNAs. Downregulation of the pro-apoptotic gene BCL2L11/BIM ( BIM) by multiple members of the cluster likely contribute to the ability of these miRNAs to block apoptosis and promote lymphomagenesis. 22, 24,25 Indeed, haploinsufficiency for this gene is known to exacerbate disease in Eμ- Myc mice. 26 Similarly, loss-of-function of the E2F1 and E2F2 transcription factors and the phosphatase and tensin homolog (PTEN) tumor suppressor, additional validated targets of the miR-17-92 cluster, 17, 27 is known to promote malignancy and autoimmunity in mice. 28-34,35 These miRNAs have also been demonstrated to target CDKN1A (p21), a cyclin-dependent kinase inhibitor which is a critical effector of cell-cycle arrest induced by p53 activation. 25, 36 Thus, high expression of the miR-17-92 cluster would be expected to impair the p53 functional axis. Finally, downregulation of the anti-angiogenic proteins thrombospondin-1 (Tsp1) and connective tissue growth factor (CTGF) likely contribute to the ability of these miRNAs to promote tumor neovascularization. 23More recent studies of the regulation of miRNAs by Myc have revealed a much broader role for this transcription factor in reprogramming miRNA expression. Through the analysis of both human and mouse models of B cell lymphoma, Chang et al.37 documented that Myc activation leads not only to induction of the miR-17-92 cluster but also to widespread repression of dozens of miRNAs. These include several miRNAs with known anti-tumorigenic activity such as the let-7 family, the miR-29 family, miR-15a/16-1, and miR-34a. 38 ChIP demonstrates that Myc associates with the core promoters of the miRNAs which it represses, suggesting that much of this downregulation is a consequence of reduced transcription of pri-miRNAs. Myc-mediated miRNA repression is critical for the ability of this oncogene to promote neoplastic cellular behavior since re-expression of miRNAs such as miR-15a/16-1, miR-22, miR-26a, miR-34a, and miR-150 dramatically suppresses tumorigenic potential in an in vivo model of Myc-mediated lymphomagenesis. Widespread Myc-mediated miRNA repression is particularly interesting given that miRNA expression has been shown to be globally reduced in many tumors 11,39 and experimental inhibition of miRNA biogenesis enhances neoplastic transformation. 40 Although there is evidence that a post-transcriptional block in miRNA processing contributes to reduced miRNA abundance in cancer, 41 the demonstration that activation of Myc, a common event in many cancers, induces broad miRNA downregulation suggests that transcriptional repression also contributes to this phenomenon. miRNAs in functional networks controlled by fusion oncoproteins Chromosomal translocations giving rise to novel fusion proteins with oncogenic activity are common in various hematopoietic malignancies and solid tumors. Several studies have reported that specific miRNA expression signatures are associated with specific translocations in acute myeloid leukemia (AML) 15, 42, 43 suggesting that fusion oncoproteins may directly influence miRNA expression. Indeed, a number of reports have recently highlighted the importance of miRNA regulation in the pro-tumorigenic activity of selected fusion oncoproteins. This is well illustrated by the functions of the fusion product of the AML1 and ETO genes, which are juxtaposed by t(8;21) translocations, the most common karyotypic abnormality in acute myeloid leukemia (AML). 44, 45 In normal myeloid progenitors, the AML1 transcription factor activates a suite of target genes that promote differentiation. The AML1/ETO fusion protein retains the ability to interact with AML1-target promoters but acts as a dominant-negative repressor, thereby promoting leukemogenesis by blocking myeloid differentiation. It has recently been demonstrated that AML1/ETO suppresses transcription of miR-223, a miRNA which plays a critical role in the differentiation of myeloid progenitors to granulocytes (). 46 AML1/ETO binds directly to the genomic locus encoding miR-223 and recruits histone deacetylases and DNA-methyltransferases, resulting in heterochromatin formation and transcriptional silencing. Earlier work demonstrated that miR-223 is expressed nearly exclusively in the hematopoietic system and is restricted to the myeloid lineage. 47 Expression of miR-223 steadily increases throughout normal granulocyte differentiation and is induced by retinoic-acid stimulated differentiation of myeloid leukemia cell lines. 48-50 Enforced expression of miR-223 in AML cell lines and patient blasts promotes granulocytic differentiation whereas inhibition of the miRNA decreases this differentiation program. 46, 49 Moreover, loss-of-function of miR-223 in mice leads to enhanced proliferation and expansion of granulocyte precursors resulting in an enlarged and hyperfunctional granulocyte compartment. 50 Based on these observations, it is likely that suppression of miR-223 expression by AML1/ETO contributes to the differentiation block and expansion of myeloid progenitors which occurs in AML. It is also notable that the critical myeloid transcription factors CCAAT-enhancer binding protein α (C/EBPα) and PU.1 both positively regulate miR-223 expression (). 46, 51 Reduced expression of this miRNA therefore likely contributes to the differentiation block resulting from loss-of-function of these transcription factors, which is also known to occur in AML. 52Translocations involving the ALL1 gene (also known as MLL1) on 11q23 are associated with acute lymphoblastic and myeloblastic leukemias and often portend poor prognosis. These rearrangements produce oncoproteins composed of ALL1 fused to a large number of possible partners, the most common of which is AF4 on 4q21. 53 A recent comparison of miRNA expression between leukemic cell lines with or without ALL1 translocations revealed a set of dysregulated miRNA candidates which may be regulated by ALL1 fusion oncoproteins. 54 Interestingly, ChIP experiments revealed that both ALL1/AF4 and Drosha could be detected at the genomic loci encoding miR-191 and miR-23a, two miRNAs which were expressed at higher levels in cells harboring ALL1 translocations. Furthermore, siRNA-mediated knockdown of ALL1/AF4 led to an accumulation of the miR-191 and miR-23a primary transcripts, suggesting a block in Drosha cleavage. Based on these observations, a model was proposed in which ALL1 fusion oncoproteins recruit Drosha to specific miRNA loci for enhanced processing and increased expression. Although additional studies are necessary to test this model and determine the functional significance of altered miRNA expression in cells with ALL1 translocations, it is notable that high expression of miR-191 is associated with poor prognosis in AML patients. 15Oncogenic fusion proteins that regulate miRNA expression are not limited to hematopoietic malignancies. Translocations in papillary thyroid cancer (PTC) frequently fuse the RET proto-oncogene, a receptor tyrosine kinase, to a variety of partner genes resulting in ligand-independent RET signaling activity. Constitutive signaling activates the mitogen activated protein kinase (MAPK) pathway which plays a prominent role in the pathogenesis of PTC. 55, 56 One of the most common translocations results in the production of the ret/PTC1 fusion protein. A recent analysis of miRNA expression in paired thyroid epithelial cell lines with or without expression of ret/PTC1 and a PTC cell line harboring an endogenous ret/PTC1 allele revealed a number of miRNAs that are both up- and downregulated as a consequence of expression of this fusion protein. 57 An overlapping of set of miRNAs were dysregulated following expression of another common activator of the MAPK cascade in papillary thyroid carcinoma, a mutant allele of the intracellular signaling kinase BRAF. 58 These findings suggest that miRNAs may participate in neoplastic transformation mediated by these oncogenic pathways although further studies are necessary to elucidate the mechanisms linking RET and MAPK signaling to miRNA expression and the functional contributions of these miRNAs to PTC pathogenesis. Control of miRNA expression by NF-kB Nuclear factor-κB (NF-κB) represents a family of transcription factors that are best known for their roles in regulating inflammation and the immune response. There is a growing appreciation that hyperactivity of the NF-κB pathway contributes to tumorigenesis. Constitutively active NF-κB signaling can enhance cancer cell proliferation, confer resistance to apoptosis, and promote angiogenesis and metastasis. 59 Accordingly, pathologic activation of this pathway has been observed in diverse malignancies including several types of lymphoma as well as breast, colon, and gastric cancers. In order to determine whether miRNAs play a role in pro-inflammatory signaling, Taganov et al. 60 examined miRNA profiles in an AML cell line following stimulation with lipopolysaccharide (LPS). Induction of three miRNAs (miR-132, miR-146, and miR-155) was observed. Analysis of the miR-146a promoter revealed the presence of functional NF-κB binding sites. Furthermore, reporter assays provided evidence that miR-146 family members target IRAK1 and TRAF6, components of the Toll-like receptor signaling pathway which is a potent inducer of NF-κB signaling. Based on these observations, the authors proposed that induction of miR-146a by NF-κB provides a mechanism for negative feedback of pro-inflammatory signaling (). Consistent with this model, expression of miR-146a or miR-146b in a breast cancer cell line reduced IRAK1 and TRAF6 expression, suppressed NF-κB activity, and inhibited in vitro cell migration and invasion, two NF-κB-regulated phenotypes. 61 Interestingly, reduced expression or function of miR-146a has been observed in hormone-refractory prostate cancer and thyroid carcinoma, 62, 63 raising the possibility that loss of this feedback mechanism occurs in these malignancies. It is particularly noteworthy that LPS-stimulation induces miR-155, one of the most highly studied oncogenic miRNAs. miR-155 is widely overexpressed in diverse tumor types including B-cell lymphoma, and breast, lung, colon and thyroid cancers 6,19, 64. Transgenic expression of miR-155 under control of the B cell specific Eμ enhancer leads to aggressive B cell malignancies 65 whereas enforced expression in hematopoietic stem cells induces a myeloproliferative state. 66 It is likely that miR-155 is directly upregulated by NF-kB signaling since a consensus binding site is present in the promoter, 67, 68 loss-of-function of NEMO, an essential component of the NF-κB pathway, blocks LPS-mediated miR-155 induction, 69 and miR-155 expression levels correlate with NF-κB pathway activity in diffuse large B-cell lymphoma. 70 These observations provide a direct link between NF-κB signaling and activation of a pro-tumorigenic miRNA. A miRNA component of the Twist-induced metastasis program Twist is a highly conserved transcription factor that was first described as a regulator of mesoderm induction in Drosophila. 71 The vertebrate ortholog of Twist is expressed at highest levels in neural crest cells and is necessary for neural tube closure and appropriate differentiation and migration of head mesenchyme. 72, 73 These events in both flies and vertebrates require cells to undergo an epithelial-to-mesenchymal transition (EMT), a process whereby cells disengage from an ordered epithelium and acquire migratory and invasive properties. It is believed that the induction of EMT in cancer cells is a critical event underlying tumor invasion and metastasis. Twist is recognized as a potent inducer of EMT and has been demonstrated to promote invasion and metastasis of human cancer cells. 74 Recently, the Weinberg laboratory identified miR-10b as a critical component of the metastatic program induced by Twist in breast cancer cells (). 75 A potential role for miR-10b in metastasis was first suggested by its high expression in metastatic but not non-metastatic breast cancer cell lines. Similarly, high expression of this miRNA in breast tumor samples correlates with metastasis-positive disease. Functional studies demonstrated that expression of miR-10b promotes invasion and metastasis in vivo. miR-10b is a direct transcriptional target of Twist, as demonstrated by ChIP, and inhibition of miR-10b blocks the ability of Twist to induce migration and invasion in poorly motile cells. Further investigation identified the anti-metastatic gene HOXD10 as a target of miR-10b, uncovering one likely mechanism through which this miRNA promotes these phenotypes. miRNAs in Tumor Suppressor Pathways p53-regulated miRNAs Loss-of-function of the p53 tumor suppressor protein is one of the most common events in human malignancies. p53 is a transcription factor that is induced in response to a variety of potentially oncogenic stimuli such as DNA damage or aberrant oncogene activation, resulting in the transactivation of genes which induce cell-cycle arrest, apoptosis, or cellular senescence. 76 A recent series of studies have expanded the repertoire of p53-target genes to include miRNAs. 77, 78, 79, 80, 81, 82 Although a variety of different approaches were used in these studies, each highlighted miRNAs belonging to the highly conserved miR-34 family as direct transcriptional targets of p53 (). These miRNAs are produced from two loci in the human genome: miR-34a at 1p36 and the miR-34b/miR-34c cluster at 11q23. The promoters of each of these miRNA transcription units harbor functional p53 binding sites, as demonstrated by reporter assays and ChIP. Moreover, ectopic expression of these miRNAs is able to induce cell-cycle arrest, apoptosis, or cellular senescence, depending on cellular context. Similarly, inhibition of miR-34 family members significantly reduces p53 dependent apoptosis in cell lines. These observations indicate that these miRNAs are important effectors of p53 activation. Interestingly, loss-of-function of miR-34 family members may represent novel mechanism through which the p53 axis is inactivated in human cancers. 1p36, the genomic locus encoding miR-34a, is frequently lost in many tumor types 83 and reduced expression of miR-34a has been observed in neuroblastoma and pancreatic cancer cells. 78, 83 Similarly, non-small cell lung tumors frequently exhibit reduced expression of miR-34b and miR-34c. 77The ability of miR-34 family members to induce anti-proliferative and pro-apoptotic effects involves the direct regulation of a large set of target genes that are related to cell-cycle control and apoptosis, including cyclin-dependent kinases, cyclins, E2F transcription factors, and the anti-apoptotic protein Bcl2. 77, 78, 79, 82 Although miR-34a has been demonstrated to have potent anti-tumorigenic activity in p53-null cells 37 in some cell lines the most robust miR-34-induced cellular responses require a functional p53 pathway. 78 Indeed, it has been demonstrated that ectopic expression of miR-34a induces p53 itself and its downstream targets. 82 While the mechanism of this positive feedback remains unclear, these observations indicate that one function of miR-34 family members is likely to reinforce and potentiate activation of a p53 response. miRNAs in PLZF tumor suppressor functions The promyelocytic leukemia zinc finger (PLZF) protein is best known for its roles in development of the hematopoietic system, although a tumor suppressor role for this protein has more recently been uncovered in melanoma pathogenesis. Whereas PLZF is normally expressed highly in melanocytes, its expression is frequently lost in melanoma cell lines and tumor samples. 84 Re-expression of PLZF in melanoma cells decreases proliferation, invasion, and migration in vitro, and tumorigenesis in xenograft assays. The regulation of miRNAs by PLZF appears to contribute to these phenotypic effects. Felicetti et al.85 observed that expression of the miR-221/222 cluster increases during melanoma progression and enforced expression of PLZF reverses this effect. Reporter assays and ChIP demonstrate that reduced expression of these miRNAs is likely a direct consequence of PLZF binding to sites upstream of the sequences encoding miR-221 and miR-222 on the human X chromosome. Enforced expression of miR-221 and miR-222 in melanoma cell lines increases cell-cycle progression, in vitro invasion and migration, anchorage-independent growth, and tumor formation. Inhibition of these miRNAs with antisense oligonucleotides has the opposite effects. Thus, loss-of-function of PLZF likely enhances melanoma progression in part through a resulting increase in expression of miR-221/222. Several targets of miR-221/222 have been characterized that likely contribute to these effects. In particular, these miRNAs are known to potently promote cell-cycle progression through their ability to downregulate the cyclin-dependent kinase inhibitor p27. 86, 87, 88, 89 Downregulation of the receptor c-kit, another validated target of miR-221 and miR-222, 90, 91 also likely plays a role in the pro-tumorigenic activity of these miRNAs as loss of c-kit expression in advanced melanoma is believed to contribute to resistance of tumor cells to apoptosis. 92Although the aforementioned examples clearly establish a role for miRNAs downstream of several of the most critical oncogenic and tumor suppressor signaling pathways, it is likely that we are just beginning to elucidate the roles of these regulatory RNAs in the networks that control cancer pathogenesis. Nevertheless, what we have learned thus far implicates specific miRNAs as potent regulators of diverse neoplastic processes including proliferation, apoptosis, invasion, and metastasis. Moreover, miRNAs may represent critical control points in frequently dysregulated pathways including those governed by Myc and p53, raising the possibility that therapeutics targeted towards these molecules might be broadly applicable to diverse malignancies. Enthusiasm for miRNA-targeted therapeutics has been bolstered by early successes in delivering miRNA mimics and inhibitors to small animals and primates. 93, 94, 95 In order to hasten clinical implementation of these strategies, additional studies are needed to functionally evaluate the consequences of miRNA expression or inhibition in cancer cells, further dissect target networks controlled by miRNAs, and establish animal models of cancers driven by miRNA gain- or loss-of-function to serve as test beds for novel therapeutic agents. Such efforts are likely to not only improve our understanding of the basic biology of cancer but also have the potential to impact patient care in the not-to-distant future. The Mendell laboratory receives support from the National Institutes of Health (R01 CA120185) and the Sol Goldman Pancreatic Cancer Research Center. O.A.K is a Life Sciences Research Foundation fellow and J.T.M. is a Rita Allen Foundation Scholar and a Leukemia and Lymphoma Society Scholar. 1. Ambros V. The functions of animal microRNAs. Nature. 2004;431:350–5. [PubMed] 2. Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, Aldler H, Rattan S, Keating M, Rai K, Rassenti L, Kipps T, Negrini M, Bullrich F, Croce CM. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A. 2002;99:15524–9. [PubMed] 3. Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM. miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005;102:13944–9. [PubMed] 4. Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004;101:2999–3004. [PubMed] 5. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6:857–66. [PubMed] 6. Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF, Lund E, Dahlberg JE. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A. 2005;102:3627–32. [PubMed] 7. Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65:6029–33. [PubMed] 8. Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu YP, van Duijse J, Drost J, Griekspoor A, Zlotorynski E, Yabuta N, De Vita G, Nojima H, Looijenga LH, Agami R. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell. 2006;124:1169–81. [PubMed] 9. Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T, Takahashi T. Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 2004;64:3753–6. [PubMed] 10. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ. RAS is regulated by the let-7 microRNA family. Cell. 2005;120:635–47. [PubMed] 11. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA, Downing JR, Jacks T, Horvitz HR, Golub TR. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8. [PubMed] 12. Marcucci G, Radmacher MD, Maharry K, Mrozek K, Ruppert AS, Paschka P, Vukosavljevic T, Whitman SP, Baldus CD, Langer C, Liu CG, Carroll AJ, Powell BL, Garzon R, Croce CM, Kolitz JE, Caligiuri MA, Larson RA, Bloomfield CD. MicroRNA expression in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1919–28. [PubMed] 13. Camps C, Buffa FM, Colella S, Moore J, Sotiriou C, Sheldon H, Harris AL, Gleadle JM, Ragoussis J. hsa-miR-210 Is induced by hypoxia and is an independent prognostic factor in breast cancer. Clin Cancer Res. 2008;14:1340–8. [PubMed] 14. Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK, Liu CG, Calin GA, Croce CM, Harris CC. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. Jama. 2008;299:425–36. [PubMed] 15. Garzon R, Volinia S, Liu CG, Fernandez-Cymering C, Palumbo T, Pichiorri F, Fabbri M, Coombes K, Alder H, Nakamura T, Flomenberg N, Marcucci G, Calin GA, Kornblau SM, Kantarjian H, Bloomfield CD, Andreeff M, Croce CM. MicroRNA signatures associated with cytogenetics and prognosis in acute myeloid leukemia. Blood. 2008;111:3183–9. [PubMed] 16. Yu SL, Chen HY, Chang GC, Chen CY, Chen HW, Singh S, Cheng CL, Yu CJ, Lee YC, Chen HS, Su TJ, Chiang CC, Li HN, Hong QS, Su HY, Chen CC, Chen WJ, Liu CC, Chan WK, Chen WJ, Li KC, Chen JJ, Yang PC. MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell. 2008;13:48–57. [PubMed] 17. O'Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435:839–43. [PubMed] 18. Ota A, Tagawa H, Karnan S, Tsuzuki S, Karpas A, Kira S, Yoshida Y, Seto M. Identification and characterization of a novel gene, C13orf25, as a target for 13q31-q32 amplification in malignant lymphoma. Cancer Res. 2004;64:3087–95. [PubMed] 19. Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103:2257–61. [PubMed] 20. Schulte JH, Horn S, Otto T, Samans B, Heukamp LC, Eilers UC, Krause M, Astrahantseff K, Klein-Hitpass L, Buettner R, Schramm A, Christiansen H, Eilers M, Eggert A, Berwanger B. MYCN regulates oncogenic MicroRNAs in neuroblastoma. Int J Cancer. 2008;122:699–704. [PubMed] 21. He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–33. [PubMed] 22. Xiao C, Srinivasan L, Calado DP, Patterson HC, Zhang B, Wang J, Henderson JM, Kutok JL, Rajewsky K. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol. 2008;9:405–14. [PubMed] 23. Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E, Furth EE, Lee WM, Enders GH, Mendell JT, Thomas-Tikhonenko A. Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet. 2006;38:1060–5. [PubMed] 24. Ventura A, Young AG, Winslow MM, Lintault L, Meissner A, Erkeland SJ, Newman J, Bronson RT, Crowley D, Stone JR, Jaenisch R, Sharp PA, Jacks T. Targeted deletion reveals essential and overlapping functions of the miR-17 through 92 family of miRNA clusters. Cell. 2008;132:875–86. [PubMed] 25. Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, Iliopoulos D, Pilozzi E, Liu CG, Negrini M, Cavazzini L, Volinia S, Alder H, Ruco LP, Baldassarre G, Croce CM, Vecchione A. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008;13:272–86. [PubMed] 26. Egle A, Harris AW, Bouillet P, Cory S. Bim is a suppressor of Myc-induced mouse B cell leukemia. Proc Natl Acad Sci U S A. 2004;101:6164–9. [PubMed] 27. Sylvestre Y, De Guire V, Querido E, Mukhopadhyay UK, Bourdeau V, Major F, Ferbeyre G, Chartrand P. An E2F/miR-20a autoregulatory feedback loop. J Biol Chem. 2007;282:2135–43. [PubMed] 28. Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet. 1998;19:348–55. [PubMed] 29. Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeham A, Itie A, Khoo W, Fukumoto M, Mak TW. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998;8:1169–78. [PubMed] 30. Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A. 1999;96:1563–8. [PubMed] 31. Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, Yoshida R, Wakeham A, Higuchi T, Fukumoto M, Tsubata T, Ohashi PS, Koyasu S, Penninger JM, Nakano T, Mak TW. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity. 2001;14:523–34. [PubMed] 32. Yamasaki L, Jacks T, Bronson R, Goillot E, Harlow E, Dyson NJ. Tumor induction and tissue atrophy in mice lacking E2F-1. Cell. 1996;85:537–48. [PubMed] 33. Field SJ, Tsai FY, Kuo F, Zubiaga AM, Kaelin WG, Jr, Livingston DM, Orkin SH, Greenberg ME. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell. 1996;85:549–61. [PubMed] 34. Murga M, Fernandez-Capetillo O, Field SJ, Moreno B, Borlado LR, Fujiwara Y, Balomenos D, Vicario A, Carrera AC, Orkin SH, Greenberg ME, Zubiaga AM. Mutation of E2F2 in mice causes enhanced T lymphocyte proliferation, leading to the development of autoimmunity. Immunity. 2001;15:959–70. [PubMed] 35. Zhu JW, Field SJ, Gore L, Thompson M, Yang H, Fujiwara Y, Cardiff RD, Greenberg M, Orkin SH, DeGregori J. E2F1 and E2F2 determine thresholds for antigen-induced T-cell proliferation and suppress tumorigenesis. Mol Cell Biol. 2001;21:8547–64. [PubMed] 36. Ivanovska I, Ball AS, Diaz RL, Magnus JF, Kibukawa M, Schelter JM, Kobayashi SV, Lim L, Burchard J, Jackson AL, Linsley PS, Cleary MA. MicroRNAs in the miR-106b family regulate p21/CDKN1A and promote cell cycle progression. Mol Cell Biol. 2008;28:2167–74. [PubMed] 37. Chang TC, Yu D, Lee YS, Wentzel EA, Arking DE, West KM, Dang CV, Thomas-Tikhonenko A, Mendell JT. Widespread microRNA repression by Myc contributes to tumorigenesis. Nat Genet. 2008;40:43–50. [PubMed] 38. Bagchi A, Papazoglu C, Wu Y, Capurso D, Brodt M, Francis D, Bredel M, Vogel H, Mills AA. CHD5 Is a Tumor Suppressor at Human 1p36. Cell. 2007;128:459–75. [PubMed] 39. Gaur A, Jewell DA, Liang Y, Ridzon D, Moore JH, Chen C, Ambros VR, Israel MA. Characterization of microRNA expression levels and their biological correlates in human cancer cell lines. Cancer Res. 2007;67:2456–68. [PubMed] 40. Kumar MS, Lu J, Mercer KL, Golub TR, Jacks T. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 2007;39:673–7. [PubMed] 41. Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev. 2006;20:2202–7. [PubMed] 42. Jongen-Lavrencic M, Sun SM, Dijkstra MK, Valk PJ, Lowenberg B. MicroRNA expression profiling in relation to the genetic heterogeneity of acute myeloid leukemia. Blood. 2008;111:5078–85. [PubMed] 43. Dixon-McIver A, East P, Mein CA, Cazier JB, Molloy G, Chaplin T, Andrew Lister T, Young BD, Debernardi S. Distinctive patterns of microRNA expression associated with karyotype in acute myeloid leukaemia. PLoS ONE. 2008;3:e2141. [PubMed] 44. Licht JD. AML1 and the AML1-ETO fusion protein in the pathogenesis of t(8;21) AML. Oncogene. 2001;20:5660–79. [PubMed] 45. Lutterbach B, Hiebert SW. Role of the transcription factor AML-1 in acute leukemia and hematopoietic differentiation. Gene. 2000;245:223–35. [PubMed] 46. Fazi F, Racanicchi S, Zardo G, Starnes LM, Mancini M, Travaglini L, Diverio D, Ammatuna E, Cimino G, Lo-Coco F, Grignani F, Nervi C. Epigenetic silencing of the myelopoiesis regulator microRNA-223 by the AML1/ETO oncoprotein. Cancer Cell. 2007;12:457–66. [PubMed] 47. Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303:83–6. [PubMed] 48. Garzon R, Pichiorri F, Palumbo T, Visentini M, Aqeilan R, Cimmino A, Wang H, Sun H, Volinia S, Alder H, Calin GA, Liu CG, Andreeff M, Croce CM. MicroRNA gene expression during retinoic acid-induced differentiation of human acute promyelocytic leukemia. Oncogene. 2007;26:4148–57. [PubMed] 49. Fazi F, Zardo G, Gelmetti V, Travaglini L, Ciolfi A, Di Croce L, Rosa A, Bozzoni I, Grignani F, Lo-Coco F, Pelicci PG, Nervi C. Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia. Blood. 2007;109:4432–40. [PubMed] 50. Johnnidis JB, Harris MH, Wheeler RT, Stehling-Sun S, Lam MH, Kirak O, Brummelkamp TR, Fleming MD, Camargo FD. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008;451:1125–9. [PubMed] 51. Fukao T, Fukuda Y, Kiga K, Sharif J, Hino K, Enomoto Y, Kawamura A, Nakamura K, Takeuchi T, Tanabe M. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell. 2007;129:617–31. [PubMed] 52. Mueller BU, Pabst T. C/EBPalpha and the pathophysiology of acute myeloid leukemia. Curr Opin Hematol. 2006;13:7–14. [PubMed] 53. van Dongen JJ, Macintyre EA, Gabert JA, Delabesse E, Rossi V, Saglio G, Gottardi E, Rambaldi A, Dotti G, Griesinger F, Parreira A, Gameiro P, Diaz MG, Malec M, Langerak AW, San Miguel JF, Biondi A. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 Concerted Action: investigation of minimal residual disease in acute leukemia. Leukemia. 1999;13:1901–28. [PubMed] 54. Nakamura T, Canaani E, Croce CM. Oncogenic All1 fusion proteins target Drosha-mediated microRNA processing. Proc Natl Acad Sci U S A. 2007;104:10980–5. [PubMed] 55. Specht MC, Barden CB, Fahey TJ., 3rd p44/p42-MAP kinase expression in papillary thyroid carcinomas. Surgery. 2001;130:936–40. [PubMed] 56. Mitsutake N, Miyagishi M, Mitsutake S, Akeno N, Mesa C, Jr, Knauf JA, Zhang L, Taira K, Fagin JA. BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis. Endocrinology. 2006;147:1014–9. [PubMed] 57. Cahill S, Smyth P, Finn SP, Denning K, Flavin R, O'Regan EM, Li J, Potratz A, Guenther SM, Henfrey R, O'Leary JJ, Sheils O. Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer. 2006;5:70. [PubMed] 58. Cahill S, Smyth P, Denning K, Flavin R, Li J, Potratz A, Guenther SM, Henfrey R, O'Leary JJ, Sheils O. Effect of BRAFV600E mutation on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Mol Cancer. 2007;6:21. [PubMed] 59. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer. 2002;2:301–10. [PubMed] 60. Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103:12481–6. [PubMed] 61. Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J, Benz CC. Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 2008 62. Lin SL, Chiang A, Chang D, Ying SY. Loss of mir-146a function in hormone-refractory prostate cancer. RNA. 2008;14:417–24. [PubMed] 63. Jazdzewski K, Murray EL, Franssila K, Jarzab B, Schoenberg DR, de la Chapelle A. Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc Natl Acad Sci U S A. 2008;105:7269–74. [PubMed] 64. He H, Olesnanik K, Nagy R, Liyanarachchi S, Prasad ML, Stratakis CA, Kloos RT, de la Chapelle A. Allelic variation in gene expression in thyroid tissue. Thyroid. 2005;15:660–7. [PubMed] 65. Costinean S, Zanesi N, Pekarsky Y, Tili E, Volinia S, Heerema N, Croce CM. Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc Natl Acad Sci U S A. 2006;103:7024–9. [PubMed] 66. O'Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, Paquette RL, Baltimore D. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205:585–94. [PubMed] 67. van den Berg A, Kroesen BJ, Kooistra K, de Jong D, Briggs J, Blokzijl T, Jacobs S, Kluiver J, Diepstra A, Maggio E, Poppema S. High expression of B-cell receptor inducible gene BIC in all subtypes of Hodgkin lymphoma. Genes Chromosomes Cancer. 2003;37:20–8. [PubMed] 68. Kluiver J, van den Berg A, de Jong D, Blokzijl T, Harms G, Bouwman E, Jacobs S, Poppema S, Kroesen BJ. Regulation of pri-microRNA BIC transcription and processing in Burkitt lymphoma. Oncogene. 2007;26:3769–76. [PubMed] 69. Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, Murphy A, Frendewey D, Valenzuela D, Kutok JL, Schmidt-Supprian M, Rajewsky N, Yancopoulos G, Rao A, Rajewsky K. Regulation of the germinal center response by microRNA-155. Science. 2007;316:604–8. [PubMed] 70. Rai D, Karanti S, Jung I, Dahia PL, Aguiar RC. Coordinated expression of microRNA-155 and predicted target genes in diffuse large B-cell lymphoma. Cancer Genet Cytogenet. 2008;181:8–15. [PubMed] 71. Baylies MK, Bate M. twist: a myogenic switch in Drosophila. Science. 1996;272:1481–4. [PubMed] 72. Chen ZF, Behringer RR. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev. 1995;9:686–99. [PubMed] 73. Soo K, O'Rourke MP, Khoo PL, Steiner KA, Wong N, Behringer RR, Tam PP. Twist function is required for the morphogenesis of the cephalic neural tube and the differentiation of the cranial neural crest cells in the mouse embryo. Dev Biol. 2002;247:251–70. [PubMed] 74. Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39. [PubMed] 75. Ma L, Teruya-Feldstein J, Weinberg RA. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature. 2007;449:682–8. [PubMed] 76. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–10. [PubMed] 77. Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, Zhai Y, Giordano TJ, Qin ZS, Moore BB, MacDougald OA, Cho KR, Fearon ER. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr Biol. 2007;17:1298–307. [PubMed] 78. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, Arking DE, Beer MA, Maitra A, Mendell JT. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell. 2007;26:745–52. [PubMed] 79. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ. A microRNA component of the p53 tumour suppressor network. Nature. 2007;447:1130–4. [PubMed] 80. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007;26:731–43. [PubMed] 81. Tarasov V, Jung P, Verdoodt B, Lodygin D, Epanchintsev A, Menssen A, Meister G, Hermeking H. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle. 2007;6:1586–93. [PubMed] 82. Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A. 2007;104:15472–7. [PubMed] 83. Welch C, Chen Y, Stallings RL. MicroRNA-34a functions as a potential tumor suppressor by inducing apoptosis in neuroblastoma cells. Oncogene. 2007;26:5017–22. [PubMed] 84. Felicetti F, Bottero L, Felli N, Mattia G, Labbaye C, Alvino E, Peschle C, Colombo MP, Care A. Role of PLZF in melanoma progression. Oncogene. 2004;23:4567–76. [PubMed] 85. Felicetti F, Errico MC, Bottero L, Segnalini P, Stoppacciaro A, Biffoni M, Felli N, Mattia G, Petrini M, Colombo MP, Peschle C, Care A. The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms. Cancer Res. 2008;68:2745–54. [PubMed] 86. Gillies JK, Lorimer IA. Regulation of p27Kip1 by miRNA 221/222 in glioblastoma. Cell Cycle. 2007;6:2005–9. [PubMed] 87. Galardi S, Mercatelli N, Giorda E, Massalini S, Frajese GV, Ciafre SA, Farace MG. miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J Biol Chem. 2007;282:23716–24. [PubMed] 88. le Sage C, Nagel R, Egan DA, Schrier M, Mesman E, Mangiola A, Anile C, Maira G, Mercatelli N, Ciafre SA, Farace MG, Agami R. Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. EMBO J. 2007;26:3699–708. [PubMed] 89. Visone R, Russo L, Pallante P, De Martino I, Ferraro A, Leone V, Borbone E, Petrocca F, Alder H, Croce CM, Fusco A. MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. Endocr Relat Cancer. 2007;14:791–8. [PubMed] 90. Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F, Liuzzi F, Lulli V, Morsilli O, Santoro S, Valtieri M, Calin GA, Liu CG, Sorrentino A, Croce CM, Peschle C. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci U S A. 2005;102:18081–6. [PubMed] 91. He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, Calin GA, Liu CG, Franssila K, Suster S, Kloos RT, Croce CM, de la Chapelle A. The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci U S A. 2005;102:19075–80. [PubMed] 92. Hussein MR, Haemel AK, Wood GS. Apoptosis and melanoma: molecular mechanisms. J Pathol. 2003;199:275–88. [PubMed] 93. Khan A, Benboubetra M, Sayyed PZ, Ng KW, Fox S, Beck G, Benter IF, Akhtar S. Sustained polymeric delivery of gene silencing antisense ODNs, siRNA, DNAzymes and ribozymes: in vitro and in vivo studies. J Drug Target. 2004;12:393–404. [PubMed] 94. Krutzfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with ‘antagomirs’ Nature. 2005;438:685–9. [PubMed] 95. Elmen J, Lindow M, Schutz S, Lawrence M, Petri A, Obad S, Lindholm M, Hedtjarn M, Hansen HF, Berger U, Gullans S, Kearney P, Sarnow P, Straarup EM, Kauppinen S. LNA-mediated microRNA silencing in non-human primates. Nature. 2008;452:896–9. [PubMed]
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