MicroRNA miR-183 Functions as an Oncogene by Targeting the Transcription Factor EGR1 and Promoting Tumor Cell Migration

Biostatistics and Bioinformatics, University of Minnesota, Minneapolis, Minnesota, USA.
Cancer Research (Impact Factor: 9.33). 12/2010; 70(23):9570-80. DOI: 10.1158/0008-5472.CAN-10-2074
Source: PubMed


The transcription factor EGR1 is a tumor suppressor gene that is downregulated in many cancer types. Clinically, loss of EGR1 translates to increased tumor transformation and subsequent patient morbidity and mortality. In synovial sarcoma, the SS18-SSX fusion protein represses EGR1 expression through a direct association with the EGR1 promoter. However, the mechanism through which EGR1 becomes downregulated in other tumor types is unclear. Here, we report that EGR1 is regulated by microRNA (miR)-183 in multiple tumor types including synovial sarcoma, rhabdomyosarcoma (RMS), and colon cancer. Using an integrative network analysis, we identified that miR-183 is significantly overexpressed in these tumor types as well as in corresponding tumor cell lines. Bioinformatic analyses suggested that miR-183 could target EGR1 mRNA and this specific interaction was validated in vitro. miR-183 knockdown in synovial sarcoma, RMS, and colon cancer cell lines revealed deregulation of a miRNA network composed of miR-183-EGR1-PTEN in these tumors. Integrated miRNA- and mRNA-based genomic analyses indicated that miR-183 is an important contributor to cell migration in these tumor types and this result was functionally validated to be occurring via an EGR1-based mechanism. In conclusion, our findings have significant implications in the mechanisms underlying EGR1 regulation in cancers. miR-183 has a potential oncogenic role through the regulation of 2 tumor suppressor genes, EGR1 and PTEN, and the deregulation of this fundamental miRNA regulatory network may be central to many tumor types.

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    • "For example, miR-22, miR-7 and miR-101 have been found to be downregulated in tumors and function as tumor suppressors (11–13), whereas miR-21 and miR-17 have been observed to be upregulated in tumors and function as oncogenes (14,15). The role of miR-183 in tumors is controversial; for instance, miR-183 has been found to be downregulated and inhibit cell migration and invasion in breast cancer and osteosarcoma (16,17); conversely, miR-183 has been revealed to be overexpressed and promote tumor progression in synovial sarcoma, rhabdomyosarcoma and colon cancer (18). However, the biological role of miR-183 in gastric cancer remains unclear. "
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    ABSTRACT: The aberrant expression of microRNA-183 (miRNA/miR-183) has been found to be involved in numerous tumor types. However, the role of miR-183 in gastric cancer pathology is unclear and requires investigation. In the present study, the miR-183 expression levels of gastric cancer cell lines and tissues obtained from gastric cancer patients were measured by reverse transcription quantitative polymerase chain reaction analysis. The effect of miR-183 on gastric cancer cell proliferation and invasion was evaluated using MTT, colony formation and Transwell assays. The target of miR-183 was identified and confirmed using a luciferase activity assay. The results revealed that miR-183 was significantly downregulated in gastric cancer cells compared with GES-1 normal gastric epithelial cells. In addition, miR-183 was reduced in gastric cancer tissues compared with adjacent normal tissues. The ectopic expression of miR-183 significantly inhibited gastric cancer cell proliferation, colony formation and invasion. Bmi-1 was also confirmed as a downstream target of miR-183 in the gastric cancer cells by western blot analysis and luciferase activity assays. In conclusion, miR-183 is downregulated in gastric cancer cells and tissues, and inhibits gastric cancer cell proliferation and invasion by targeting Bmi-1. Therefore, targeting miR-183 may be a potential therapeutic strategy in gastric cancer patients.
    Oncology letters 11/2014; 8(5):2345-2351. DOI:10.3892/ol.2014.2504 · 1.55 Impact Factor
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    • "As exemplified by miR-7-5p that was down-regulated in TCPTC and CPTC, its cognate mRNA targets cardiotrophin-like cytokine factor 1 (CLCF1) and insulin receptor substrate 2 (IRS2) were noted linking immune responses in the PTC direct miRNA−target network with highest scores, of which each mRNA was also entangled in the PTC ceRNA network mediated by miR-7-5p, consistent with a recent finding that miR-7-5p:IRS2 interaction is responsible for migration and invasion in melanoma cells55. Alternatively, despite the oncogenic potential in several neoplastic contexts565758, miR-182-5p, miR-183-5p, and miR-328-5p, which showed significant up-regulation in FPTC, were remarked for their capability of tuning immune responses from these networks in thyroid cancer. "
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    ABSTRACT: Papillary thyroid carcinoma (PTC) is a common endocrine malignancy with low death rate but increased incidence and recurrence in recent years. MicroRNAs (miRNAs) are small non-coding RNAs with diverse regulatory capacities in eukaryotes and have been frequently implied in human cancer. Despite current progress, however, a panoramic overview concerning miRNA regulatory networks in PTC is still lacking. Here, we analyzed the expression datasets of PTC from The Cancer Genome Atlas (TCGA) Data Portal and demonstrate for the first time that immune responses are significantly enriched and under specific regulation in the direct miRNA-target network among distinctive PTC variants to different extents. Additionally, considering the unconventional properties of miRNAs, we explore the protein-coding competing endogenous RNA (ceRNA) and the modulatory networks in PTC and unexpectedly disclose concerted regulation of immune responses from these networks. Interestingly, miRNAs from these conventional and unconventional networks share general similarities and differences but tend to be disparate as regulatory activities increase, coordinately tuning the immune responses that in part account for PTC tumor biology. Together, our systematic results uncover the intensive regulation of immune responses underlain by miRNA-mediated networks in PTC, opening up new avenues in the management of thyroid cancer.
    Scientific Reports 09/2014; 4:6495. DOI:10.1038/srep06495 · 5.58 Impact Factor
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    • "Other evidenced targets for miR-183 confirm the antiapoptotic and prooncogenic role of miR-183 by inhibiting early growth response protein 1 (EGR1) ( Sarver et al., 2010 ) and its effect, promoting cerebellar granule neuron (CGN) progenitor proliferation in a cooperative manner with the hedgehog signaling pathway ( Zhang et al., 2013 ). miR-92a is a member of the miR-17/92 cluster, one of the best studied miRNA clusters, which is involved in cell cycle, proliferation, apoptosis, and other crucial processes , such as normal embryo development ( Mogilyansky and Rigoutsos, 2013 ). "
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    ABSTRACT: Abstract During early and late embryo neurodevelopment, a large number of molecules work together in a spatial and temporal manner to ensure the adequate formation of an organism. Diverse signals participate in embryo patterning and organization synchronized by time and space. Among the molecules that are expressed in a temporal and spatial manner, and that are considered essential in several developmental processes, are the microRNAs (miRNAs). In this review, we highlight some important aspects of the biogenesis and function of miRNAs as well as their participation in ectoderm commitment and their role in central nervous system (CNS) development. Instead of giving an extensive list of miRNAs involved in these processes, we only mention those miRNAs that are the most studied during the development of the CNS as well as the most likely mRNA targets for each miRNA and its protein functions.
    Reviews in the neurosciences 06/2014; 25(5). DOI:10.1515/revneuro-2014-0014 · 3.33 Impact Factor
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