title: miRNA signatures associate with pathogenesis and progression of osteosarcoma.
abstract: Osteosarcoma remains a leading cause of cancer death in adolescents. Treatment paradigms and survival rates have not improved in two decades. Driving the lack of therapeutic inroads, the molecular etiology of osteosarcoma remains elusive. MicroRNAs (miRNAs) have demonstrated far-reaching effects on the cellular biology of development and cancer. Their role in osteosarcomagenesis remains largely unexplored. Here we identify for the first time an miRNA signature reflecting the pathogenesis of osteosarcoma from surgically procured samples from human patients. The signature includes high expression of miR-181a,miR-181b, and miR-181c as well as reduced expression of miR-16, miR-29b, and miR-142-5p. We also demonstrate that miR-181b and miR-29b exhibit restricted expression to distinct cell populations in the tumor tissue. Further, higher expression of miR-27a and miR-181c* in pre-treatment biopsy samples characterized patients who developed clinical metastatic disease. In addition, higher expression of miR-451 and miR-15b in pre-treatment samples correlated with subsequent positive response to chemotherapy. In vitro and in vivo functional validation in osteosarcoma cell lines confirmed the tumor suppressive role of miR-16 and the pro-metastatic role of miR-27a. Furthermore, predicted target genes for miR-16 and miR-27a were confirmed as down-regulated by real-time PCR. Affymetrix array profiling of cDNAs from the osteosarcoma specimens and controls were interrogated according to predicted targets of miR-16, miR142-5p, miR-29b, miR-181a/b, and miR-27a. This analysis revealed positive and negative correlations highlighting pathways of known importance to osteosarcoma, as well as novel genes. Thus, our findings establish a miRNA signature associated with pathogenesis of osteosarcoma as well as critical pre-treatment biomarkers of metastasis and responsiveness to therapy.
authors.affiliation: Department of Orthopaedics and Center for Children's Cancer Research, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Jones
authors.forename: Zaidoun
authors.initials: Z
authors.lastname: Salah
authors.forename: Sara
authors.initials: S
authors.lastname: Del Mare
authors.forename: Marco
authors.initials: M
authors.lastname: Galasso
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Kimberly
authors.initials: K
authors.lastname: LeBlanc
authors.forename: Jeff
authors.initials: J
authors.lastname: Palatini
authors.forename: R Lor
authors.initials: RL
authors.lastname: Randall
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.forename: Rami I
authors.initials: RI
authors.lastname: Aqeilan
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D041681:NIH 3T3 Cells; D012516:Osteosarcoma / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics
chemical_list: C505362:MIRN16 microRNA, human; C531388:MIRN27 microRNA, human; C532045:MIRN29a microRNA, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs