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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    • "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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    • "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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