Article

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: 9.28). 12/2010; 70(23):9570-80. DOI: 10.1158/0008-5472.CAN-10-2074
Source: PubMed

ABSTRACT 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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    • "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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