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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Available from: Lihua li, Oct 27, 2015
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    • "RECK, MT1-MMP, and EMMPRIN mRNAs and miRNAs were examined in a LightCycler 480 (Roche Applied Science, Indianapolis, IN) by using QuantiTect SYBR Green PCR kit according to the manufacturer's protocol (Qiagen). GAPDH and U6 were used as internal controls to check the efficiency of cDNA synthesis and PCR amplification [25]. The PCR primers were RECK: "
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    ABSTRACT: Cell surface localized membrane type 1-matrix metalloproteinase (MT1-MMP) plays an important role in physiological and pathological processes and its function can be regulated by proteins such as RECK. We examined the ability of miR-182 (one of the miR-183 cluster miRNAs), which can target RECK, to control cell surface MT1-MMP activity. Expression of RECK mRNA and protein was increased with anti-miRs to miR-182, miR-183 or miR-96 in HT1080 fibrosarcoma cells, but, decreased RECK mRNA and increased its protein in the benign prostatic hyperplasia cell line BPH-1. Treatment of BPH-1 and HT-1080 cells with the anti-miRs did not change the level of cell surface MT1-MMP activity, nor their rate of migration in an in vitro wound-healing assay. Trichostatin A (TSA) did not increase the level of RECK, but blocked cell surface MT1-MMP activity and decreased cell motility. Anti-miRs mediated increased RECK levels did not interfere with cell surface MT1-MMP function, and TSA may block cell surface localization of MT1-MMP by a mechanism independent of RECK.
    American Journal of Cancer Research 09/2015; 5(9):2918-2928. · 4.17 Impact Factor
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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.
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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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