MicroRNA miR-183 functions as an oncogene by targeting the transcription factor EGR1 and promoting tumor cell migration.

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.

• Authors: Aaron L Sarver, Lihua Li, Subbaya Subramanian
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 23 Pg. 9570-80 (Dec 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 21118966 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3' Untranslated Regions
• EGR1 protein, human
• Early Growth Response Protein 1
• MIRN183 microRNA, human
• Membrane Proteins
• MicroRNAs
• Oligonucleotides, Antisense
• RNA, Messenger
• TPTE protein, human
• PTEN Phosphohydrolase

Topics

• 3' Untranslated Regions (genetics)
• Binding Sites (genetics)
• Blotting, Western
• Cell Line, Tumor
• Cell Movement (genetics)
• Early Growth Response Protein 1 (genetics, metabolism)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• HCT116 Cells
• Humans
• Membrane Proteins (genetics, metabolism)
• MicroRNAs (genetics, metabolism)
• Neoplasms (genetics, metabolism, pathology)
• Oligonucleotides, Antisense (genetics)
• Oncogenes (genetics)
• PTEN Phosphohydrolase (genetics, metabolism)
• RNA Interference
• RNA, Messenger (genetics, metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction (genetics)