title: Genomic amplification upregulates estrogen-related receptor alpha and its depletion inhibits oral squamous cell carcinoma tumors in vivo.
abstract: The ESRRA gene encodes a transcription factor and regulates several genes, such as WNT11 and OPN, involved in tumorigenesis. It is upregulated in several cancers, including OSCC. We have previously shown that the tumor suppressor miR-125a targets ESRRA, and its downregulation causes upregulation of ESRRA in OSCC. Upregulation of ESRRA in the absence of downregulation of miR-125a in a subset of OSCC samples suggests the involvement of an alternative mechanism. Using TaqMan(®) copy number assay, here we report for the first time that the genomic amplification of ESRRA causes its upregulation in a subset of OSCC samples. Ectopic overexpression of ESRRA led to accelerated cell proliferation, anchorage-independent cell growth and invasion, and inhibited apoptosis. Whereas, knockdown of ESRRA expression by siRNA led to reduced cell proliferation, anchorage-independent cell growth and invasion, and accelerated apoptosis. Furthermore, the delivery of a synthetic biostable ESRRA siRNA to OSCC cells resulted in regression of xenografts in nude mice. Thus, the genomic amplification of ESRRA is another novel mechanism for its upregulation in OSCC. Based on our in vitro and in vivo experiments, we suggest that targeting ESRRA by siRNA could be a novel therapeutic strategy for OSCC and other cancers.
authors.affiliation: Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore 560012, India.
authors.forename: Ankana
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: Department of Surgery, Bangalore Institute of Oncology, Bangalore 560027, India.
authors.forename: Shivananda
authors.initials: S
authors.lastname: Swamy
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, India.
authors.forename: Arun
authors.initials: A
authors.lastname: Kumar
mesh_terms: D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D023281:Genomics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D000097983:ERRalpha Estrogen-Related Receptor; C531888:MIRN125 microRNA, human