Oncogene database

406979

MIR19A

microRNA 19a;MIR19A;microRNA 19a

-

13q31.3

ncRNA

To date, more than 200 microRNAs have been described in humans; however, the precise functions of these regulatory, non-coding RNAs remains largely obscure. One cluster of microRNAs, the mir-17-92 polycistron, is located in a region of DNA that is amplified in human B-cell lymphomas. Here we compared B-cell lymphoma samples and cell lines to normal tissues, and found that the levels of the primary or mature microRNAs derived from the mir-17-92 locus are often substantially increased in these cancers. Enforced expression of the mir-17-92 cluster acted with c-myc expression to accelerate tumour development in a mouse B-cell lymphoma model. tumours derived from haematopoietic stem cells expressing a subset of the mir-17-92 cluster and c-myc could be distinguished by an absence of apoptosis that was otherwise prevalent in c-myc-induced lymphomas. Together, these studies indicate that non-coding RNAs, specifically microRNAs, can modulate tumour formation, and implicate the mir-17-92 cluster as a potential human oncogene.

Micro RNAs (miRNAs) are non-coding small RNAs and constitute a novel class of negative gene regulators that are found in both plants and animals. Several miRNAs play crucial roles in cancer cell growth. To identify miRNAs specifically deregulated in anaplastic thyroid cancer (ATC) cells, we performed a comprehensive analysis of miRNA expressions in ARO cells and primary thyrocytes using miRNA microarrays. MiRNAs in a miR-17-92 cluster were overexpressed in ARO cells. We confirmed the overexpression of those miRNAs by Northern blot analysis in ARO and FRO cells. In 3 of 6 clinical ATC samples, miR-17-3p and miR-17-5p were robustly overexpressed in cancer lesions compared to adjacent normal tissue. To investigate the functional role of these miRNAs in ATC cells, ARO and FRO cells were transfected with miRNA inhibitors, antisense oligonucleotides containing locked nucleic acids. Suppression of miR-17-3p caused complete growth arrest, presumably due to caspase activation resulting in apoptosis. MiR-17-5p or miR-19a inhibitor also induced strong growth reduction, but only miR-17-5p inhibitor led to cellular senescence. On the other hand, miR-18a inhibitor only moderately attenuated the cell growth. Thus, we have clarified functional differences among the members of the cluster in ATC cells. In conclusion, these findings suggest that the miR-17-92 cluster plays an important role in certain types of ATCs and could be a novel target for ATC treatment.

The miR-17 approximately 92 cluster is frequently amplified or overexpressed in human cancers and has emerged as the prototypical oncogenic polycistron microRNA (miRNA). miR-17 approximately 92 is a direct transcriptional target of c-Myc, and experiments in a mouse model of B-cell lymphomas have shown cooperation between these two oncogenes. However, both the molecular mechanism underlying this cooperation and the individual miRNAs that are responsible for it are unknown. By using a conditional knockout allele of miR-17 approximately 92, we show here that sustained expression of endogenous miR-17 approximately 92 is required to suppress apoptosis in Myc-driven B-cell lymphomas. Furthermore, we show that among the six miRNAs that are encoded by miR-17 approximately 92, miR-19a and miR-19b are absolutely required and largely sufficient to recapitulate the oncogenic properties of the entire cluster. Finally, by combining computational target prediction, gene expression profiling, and an in vitro screening strategy, we identify a subset of miR-19 targets that mediate its prosurvival activity.

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 Emu-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.

MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17 approximately 92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-alpha (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.

MicroRNAs (miRNAs) have emerged as novel cancer genes. In particular, the miR-17-92 cluster, containing six individual miRNAs, is highly expressed in haematopoietic cancers and promotes lymphomagenesis in vivo. Clinical use of these findings hinges on isolating the oncogenic activity within the 17-92 cluster and defining its relevant target genes. Here we show that miR-19 is sufficient to promote leukaemogenesis in Notch1-induced T-cell acute lymphoblastic leukaemia (T-ALL) in vivo. In concord with the pathogenic importance of this interaction in T-ALL, we report a novel translocation that targets the 17-92 cluster and coincides with a second rearrangement that activates Notch1. To identify the miR-19 targets responsible for its oncogenic action, we conducted a large-scale short hairpin RNA screen for genes whose knockdown can phenocopy miR-19. Strikingly, the results of this screen were enriched for miR-19 target genes, and include Bim (Bcl2L11), AMP-activated kinase (Prkaa1) and the phosphatases Pten and PP2A (Ppp2r5e). Hence, an unbiased, functional genomics approach reveals a coordinate clampdown on several regulators of phosphatidylinositol-3-OH kinase-related survival signals by the leukaemogenic miR-19.

The miR-17~92 cluster is a potent microRNA-encoding oncogene. Here, we show that miR-17~92 synergizes with loss of Rb family members to promote retinoblastoma. We observed miR-17~92 genomic amplifications in murine retinoblastoma and high expression of miR-17~92 in human retinoblastoma. While miR-17~92 was dispensable for mouse retinal development, miR-17~92 overexpression, together with deletion of Rb and p107, led to rapid emergence of retinoblastoma with frequent metastasis to the brain. miR-17~92 oncogenic function in retinoblastoma was not mediated by a miR-19/PTEN axis toward apoptosis suppression, as found in lymphoma/leukemia models. Instead, miR-17~92 increased the proliferative capacity of Rb/p107-deficient retinal cells. We found that deletion of Rb family members led to compensatory up-regulation of the cyclin-dependent kinase inhibitor p21Cip1. miR-17~92 overexpression counteracted p21Cip1 up-regulation, promoted proliferation, and drove retinoblastoma formation. These results demonstrate that the oncogenic determinants of miR-17~92 are context-specific and provide new insights into miR-17~92 function as an RB-collaborating gene in cancer.

BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3) is an oncogene known to promote tumour metastasis, especially in colorectal cancer (CRC). Here, we demonstrate that the miR-21, miR-17 and miR-19a expressions induced by PRL-3 are involved in the proliferation and metastasis of colon cancer. METHODS: Microarray analysis and quantitative reverse-transcription polymerase chain reactions (qRT-PCR) were used to investigate the changes in miRNA expression due to the overexpression of PRL-3. Transwell chamber invasion assays, CCK-8 proliferation assays and RNA interference assays were used to explore the effects of PRL-3 on miR-21, miR-17 and miR-19a expression in colon cancer cells. Immunohistochemistry and qRT-PCR were performed in colon cancer tissues to evaluate the expression of PRL-3, signal transducer and activator of transcription 3 (STAT3), miR-21, miR-17 and miR-19a. RESULTS: Our study demonstrated that the overexpression of PRL-3 in colon cancer cells induced the expression of miR-21, miR-17 and miR-19a by activating STAT3. Subsequently, these microRNAs contributed to the increased proliferation and invasiveness of the colon cancer cells. Positive correlations between PRL-3 and these microRNAs were also observed in matched primary colon cancer tissues and metastatic lesions. CONCLUSION: miR-21, miR-17 and miR-19a induced by PRL-3 contribute to the proliferation and invasion of colon cancer.

BACKGROUND: The application of microRNAs (miRNAs) as potential biomarkers and therapy targets has been widely investigated in many kinds of cancers. The discovery of tumor associated miRNAs in serum of patients supported the use of plasma/serum miRNAs as noninvasive means of cancer detection. However, the aberrant expression of miRNAs in bladder cancer patients and their intensive roles and mechanisms in bladder cancer are poorly understood. METHODS: Taqman probe stem-loop real-time PCR was used to accurately measure the levels of miR-19a in bladder cancer cell lines, 100 pairs of bladder cancer tissues and the adjacent non-neoplastic tissues and also the plasma collected from bladder cancer patients and normal controls. miR-19a mimics and inhibitors were transfected into bladder cancer cells to investigate its role on regulating cell proliferation which was measured by CCK-8 and colony formation assay. The target of miR-19a was identified by western blot and whether its regulatory role depends on its target was improved by a rescue experiment with miR-19a mimic and PTEN expression plasmid. RESULTS: miR-19a was significantly up-regulated in bladder cancer tissues and high-level of miR-19a was correlative with more aggressive phenotypes of bladder cancer. Meanwhile, gain or loss of function of miR-19a demonstrated that miR-19a can promote cell growth of bladder cancer cells and the further mechanism studies indicated that its oncogenic role was dependent on targeting PTEN. Furthermore, investigation of miR-19a expression in the plasma of bladder cancer patients showed that miR-19a was also increased in plasma of bladder cancer patients which strongly supported miR-19a could be developed as potential diagnostic marker of bladder cancer. CONCLUSIONS: Our data indicated that miR-19a might act as an oncogenic microRNA in bladder cancer and was significantly up-regulated in bladder cancer carcinogenesis. The oncogenic role of miR19a in bladder cancer was dependent on targeting PTEN.