title: MicroRNA-125a reduces proliferation and invasion of oral squamous cell carcinoma cells by targeting estrogen-related receptor α: implications for cancer therapeutics.
abstract: Estrogen-related receptor α (ESRRA) functions as a transcription factor and regulates the expression of several genes, such as WNT11 and OPN. Up-regulation of ESRRA has been reported in several cancers. However, the mechanism underlying its up-regulation is unclear. Furthermore, the reports regarding the role and regulation of ESRRA in oral squamous cell carcinoma (OSCC) are completely lacking. Here, we show that tumor suppressor miR-125a directly binds to the 3'UTR of ESRRA and represses its expression. Overexpression of miR-125a in OSCC cells drastically reduced the level of ESRRA, decreased cell proliferation, and increased apoptosis. Conversely, the delivery of an miR-125a inhibitor to these cells drastically increased the level of ESRRA, increased cell proliferation, and decreased apoptosis. miR-125a-mediated down-regulation of ESRRA impaired anchorage-independent colony formation and invasion of OSCC cells. Reduced cell proliferation and increased apoptosis of OSCC cells were dependent on the presence of the 3'UTR in ESRRA. The delivery of an miR-125a mimic to OSCC cells resulted in marked regression of xenografts in nude mice, whereas the delivery of an miR-125a inhibitor to OSCC cells resulted in a significant increase of xenografts and abrogated the tumor suppressor function of miR-125a. We observed an inverse correlation between the expression levels of miR-125a and ESRRA in OSCC samples. In summary, up-regulation of ESRRA due to down-regulation of miR-125a is not only a novel mechanism for its up-regulation in OSCC, but decreasing the level of ESRRA by using a synthetic miR-125a mimic may have an important role in therapeutic intervention of OSCC and other cancers.
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012 and.
authors.forename: Ankana
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: Department of Surgery, Bangalore Institute of Oncology, Bangalore 560027, India.
authors.forename: Swamy
authors.initials: S
authors.lastname: Shivananda
authors.affiliation: Department of Surgery, Bangalore Institute of Oncology, Bangalore 560027, India.
authors.forename: Kodaganur S
authors.initials: KS
authors.lastname: Gopinath
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012 and. Electronic address: karun@mrdg.iisc.ernet.in.
authors.forename: Arun
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001374:Azacitidine / Q000031:analogs & derivatives / Q000737:chemistry; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000077209:Decitabine; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D000077209:Decitabine; D001374:Azacitidine
keywords: Cancer Biology; Cell Proliferation; Head and Neck Squamous Cell Carcinoma; MicroRNA (miRNA); Post-transcriptional Regulation