Recent studies have revealed the importance of multiple microRNAs (miRNAs) in promoting tumorigenesis, among which mir-17-92/Oncomir-1 exhibits potent oncogenic activity. Genomic amplification and elevated expression of mir-17-92 occur in several human B-cell lymphomas, and enforced mir-17-92 expression in mice cooperates with c-myc to promote the formation of B-cell lymphomas. Unlike classic protein-coding oncogenes, mir-17-92 has an unconventional gene structure, where one primary transcript yields six individual miRNAs. Here, we functionally dissected the individual components of mir-17-92 by assaying their tumorigenic potential in vivo. Using the Em-myc model of mouse B-cell lymphoma, we identified miR-19 as the key oncogenic component of mir-17-92, both necessary and sufficient for promoting c-myc-induced lymphomagenesis by repressing apoptosis. The oncogenic activity of miR-19 is at least in part due to its repression of the tumor suppressor Pten. Consistently, miR-19 activates the Akt-mTOR (mammalian target of rapamycin) pathway, thereby functionally antagonizing Pten to promote cell survival. Our findings reveal the essential role of miR-19 in mediating the oncogenic activity of mir-17-92, and implicate the functional diversity of mir-17-92 components as the molecular basis for its pleiotropic effects during tumorigenesis.

MicroRNAs (miRNAs) are an abundant class of small non-coding RNAs (ncRNAs) that function to regulate gene expression at the post-transcriptional level. Although their functions were originally described during normal development, miRNAs have emerged as integral components of the oncogenic and tumor suppressor network, regulating nearly all cellular processes altered during tumor formation. In particular, mir-17-92, a miRNA polycistron also known as oncomir-1, is among the most potent oncogenic miRNAs. Genomic amplification and elevated expression of mir-17-92 were both found in several human B-cell lymphomas, and its enforced expression exhibits strong tumorigenic activity in multiple mouse tumor models. mir-17-92 carries out pleiotropic functions during both normal development and malignant transformation, as it acts to promote proliferation, inhibit differentiation, increase angiogenesis and sustain cell survival. Unlike most protein coding genes, mir-17-92 is a polycistronic miRNA cluster that contains multiple miRNA components, each of which has a potential to regulate hundreds of target mRNAs. This unique gene structure of mir-17-92 may underlie the molecular basis for its pleiotropic functions in a cell type and context dependent manner. Here we review the recent literature on the functional studies of mir-17-92, and highlight its potential impacts on the oncogene network. These findings on mir-17-92 indicate that miRNAs, together with protein coding genes, are integrated components of the molecular pathways that regulate tumor development and tumor maintenance.

IntroductionCD4 ϩ T cells are essential components of the adaptive immune system that regulate immune responses against foreign pathogens and tumors. Upon antigen recognition, naive CD4 ϩ T cells undergo activation and expansion, and then contract via programmed cell death. 1 Specific antigen challenges also induce CD4 ϩ T cells to differentiate into distinct Th cell lineages characterized by unique cytokine production profiles. 2 Among these lineages, Th1 cells, the differentiation of which is controlled by the master transcription factor T-bet, 3 are specialized for the clearance of intracellular infections and are implicated as the major effectors against tumors. 4 In addition, the conversion of effector T cells to Foxp3 ϩ inducible regulatory T cells (iTregs) is an important mechanism used to balance immune responses 5 that is exploited by tumors as a strategy for immune evasion. 6 Whereas the protein-based regulatory machinery that operates during the T-cell response has been vigorously explored, we have recently become aware of a novel and crucial element modulating T-cell function: miRNA. 7,8 miRNAs are 18-to 24-nucleotide noncoding RNAs that regulate gene expression by destabilizing target mRNAs, leading to mRNA degradation and/or translational repression. 9 Recent studies suggest that miRNA-mediated gene regulation represents a fundamental layer of posttranscriptional regulatory programs in metazoan genomes. 10 Global disruption of miRNAs caused by defective biogenesis had profound effects on the development of B cells, 11 Th1/Th2 differentiation, 12,13 and Treg function. 14,15 In addition to these demonstrations of the importance of miRNA biogenesis in general, accumulating evidence shows that many specific miRNAs are differentially regulated in hematopoietic lineages and play important roles in controlling the development and function of immune cells. 7,8,[16][17][18] One such regulator is the miR-17-92 cluster.This cluster of miRNAs is encoded by a polycistronic miRNA gene and generates a single transcript that yields 6 individual mature miRNAs. These miRNAs are categorized into 3 families based on sequence homology: the miR-17 family (miR-17, miR-20, and miR-18a), the miR-19 family (miR-19a and miR-19b), and the miR-25 family (miR-92a; supplemental Figure 1A, available on the Blood Web site; see the Supplemental Materials link at the top of the online article). miR-17-92 is well recognized as an "onco-miR" because of its genomic amplification in certain tumor tissues and its potent acceleration of c-My-induced B-cell lymphoma. 19 Genetic ablation has clearly established the critical roles of miR-17-92 in embryonic development. 20 In immune cells, miR-17-92 plays an integral part in the development of myeloid cells and B cells. 20,21 Mice with germline deletion of miR-17-92 exhibit a severe defect in adult B-cell development with an augmentation of apoptosis in the pro-B-cell fraction and consequently a blockade at the pro-B to pre-B transition. 20 In addition, transgenic mice overexpressing the miR-...

Neoplastic transformation is caused by accumulation of genetic lesions that ultimately convert normal cells into tumor cells with uncontrolled proliferation and survival, unlimited replicative potential, and invasive growth. Emerging evidence has highlighted the functional importance of non-coding RNAs, particularly microRNAs (miRNAs), in the initiation and progression of tumor development. The mir-17-92 miRNA is among the best characterized miRNA oncogenes, whose genomic amplification or aberrant elevation are frequently observed in a variety of tumor types. Unlike protein-coding oncogenes, where one transcript produces one protein, mir-17-92 encodes a polycistronic miRNA transcript that yields six individual miRNA components. This unique gene structure, shared by many important miRNA oncogenes and tumor suppressors, underlies the unique functionality of mir-17-92 in a cell type and context dependent manner. Recent functional dissection of mir-17-92 indicates that individual mir-17-92 components perform distinct biological functions, which collectively regulate multiple related cellular processes during development and disease. The structural complexity of mir-17-92 as a polycistronic miRNA oncogene, along with the complex mode of interactions among its components, constitute the molecular basis for its unique functional complexity during normal and tumor development

mir-17-92, a potent polycistronic oncomir, encodes six mature miRNAs with complex modes of interactions. In the Eμ-myc Burkitt’s lymphoma model, mir-17-92 exhibits potent oncogenic activity by repressing c-Myc-induced apoptosis, primarily through its miR-19 components. Surprisingly, mir-17-92 also encodes the miR-92 component that negatively regulates its oncogenic cooperation with c-Myc. This miR-92 effect is, at least in part, mediated by its direct repression of Fbw7, which promotes the proteosomal degradation of c-Myc. Thus, overexpressing miR-92 leads to aberrant c-Myc increase, imposing a strong coupling between excessive proliferation and p53-dependent apoptosis. Interestingly, miR-92 antagonizes the oncogenic miR-19 miRNAs; and such functional interaction coordinates proliferation and apoptosis during c-Myc-induced oncogenesis. This miR-19:miR-92 antagonism is disrupted in B-lymphoma cells that favor a greater increase of miR-19 over miR-92. Altogether, we suggest a new paradigm whereby the unique gene structure of a polycistronic oncomir confers an intricate balance between oncogene and tumor suppressor crosstalk.DOI: http://dx.doi.org/10.7554/eLife.00822.001