title: MicroRNA-608 and microRNA-34a regulate chordoma malignancy by targeting EGFR, Bcl-xL and MET.
abstract: Chordomas are rare malignant tumors that originate from the notochord remnants and occur in the skull base, spine and sacrum. Due to a very limited understanding of the molecular pathogenesis of chordoma, there are no adjuvant and molecular therapies besides surgical resection and radiation therapy. microRNAs (miRNAs) are small noncoding regulatory RNA molecules with critical roles in cancer. The role of miRNAs in chordomas is mostly unknown. We uncover microRNA-608 (miR-608) and microRNA-34a (miR-34a) as novel tumor suppressive microRNAs that regulate malignancy in chordoma. We find that miR-608 and miR-34a expressions are downregulated in human chordoma cell lines and primary cells at least partially via alteration of their genes' copy numbers. We identify the commonly deregulated oncogenes EGFR and Bcl-xL as direct targets of miR-608 and the receptor tyrosine kinase MET as direct target of miR-34a. We show that EGFR and MET activations promote chordoma cell proliferation and invasion and that pharmacological inhibition of EGFR and MET inhibits chordoma cell proliferation and survival. We demonstrate that restoration of miR-608 and miR-34a inhibits cell proliferation and invasion and induces apoptosis in chordoma cells. We find that miR-34a inversely correlates with MET expression and miR-608 inversely correlates with EGFR expression in chordoma cells. These findings demonstrate for the first time that miR-608 and miR-34a regulate chordoma malignancy by regulating EGFR, MET and Bcl-xL.
authors.affiliation: Departments of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.affiliation: Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Deric
authors.initials: D
authors.lastname: Park
authors.affiliation: Departments of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States of America; Department of Neurology, University of Virginia, Charlottesville, Virginia, United States of America; Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America.
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002817:Chordoma / Q000235:genetics / Q000473:pathology*; D015536:Down-Regulation / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: C522425:MIRN34 microRNA, human; C000591804:MIRN608 microRNA, human; D035683:MicroRNAs; D051020:bcl-X Protein; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met