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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Cell Cycle. Author manuscript; available in PMC Aug 15, 2009.
Published in final edited form as:
Published online Aug 17, 2008.
PMCID: PMC2654364
NIHMSID: NIHMS92599

Functional integration of microRNAs into oncogenic and tumor suppressor pathways

Abstract

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

Introduction

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.11-16

Several 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 (Figure 1A). 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

Figure 1
Functional integration of miRNAs into oncogenic and tumor suppressor pathways. Transcription factors including Myc (A), the AML1-ETO fusion oncoprotein (B), NF-κB (C), Twist (D), and p53 (E) directly activate and repress miRNA expression to influence ...

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.23

More 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 (Figure 1B).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 (Figure 1B).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.52

Translocations 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.15

Oncogenic 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 (Figure 1C). 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 cancers6,19, 64. Transgenic expression of miR-155 under control of the B cell specific Eμ enhancer leads to aggressive B cell malignancies65 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 (Figure 1D).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 (Figure 1E). 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 types83 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.77

The 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 cells37 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.92

Concluding Remarks

Although 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.

Acknowledgments

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.

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