title: miR-181a Targets RGS16 to Promote Chondrosarcoma Growth, Angiogenesis, and Metastasis.
abstract: Chondrosarcoma is the most common primary malignant bone tumor in adults, has no effective systemic treatment, and patients with this disease have poor survival. Altered expression of microRNA (miR) is involved in tumorigenesis; however, its role in chondrosarcoma is undetermined. miR-181a is overexpressed in high-grade chondrosarcoma, is upregulated by hypoxia, and increases VEGF expression. Here, the purpose was to determine the mechanism of miR-181a regulation of VEGF, determine whether miR-181a overexpression promotes tumor progression, and to evaluate an antagomir-based approach for chondrosarcoma treatment. Therapeutic inhibition of miR-181a decreased expression of VEGF and MMP1 in vitro, and angiogenesis, MMP1 activity, tumor growth, and lung metastasis, all by more than 50%, in a xenograft mouse model. A target of miR-181a is a regulator of G-protein signaling 16 (RGS16), a negative regulator of CXC chemokine receptor 4 (CXCR4) signaling. CXCR4 signaling is increased in chondrosarcoma, its expression is also increased by hypoxia, and is associated with angiogenesis and metastasis; however, receptor blockade is only partially effective. RGS16 expression is restored after miR-181a inhibition and partially accounts for the antiangiogenic and antimetastatic effects of miR-181a inhibition. These data establish miR-181a as an oncomiR that promotes chondrosarcoma progression through a new mechanism involving enhancement of CXCR4 signaling by inhibition of RGS16.
  
  
  CONCLUSIONS
  Targeting miR-181a can inhibit tumor angiogenesis, growth, and metastasis, thus suggesting the possibility of antagomir-based therapy in chondrosarcoma.
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Sun
authors.affiliation: Orthopaedic Research, Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Cherie
authors.initials: C
authors.lastname: Charbonneau
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Lei
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island.
authors.forename: Qian
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Warren Alpert Medical School of Brown University and Rhode Island Hospital, Providence, Rhode Island. Providence Veterans Administration Medical Center, Providence, Rhode Island. Richard_Terek@Brown.edu.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Terek
mesh_terms: D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002813:Chondrosarcoma / Q000378:metabolism / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary* / Q000628:therapy; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D060787:Neoplasm Grading; D009389:Neovascularization, Pathologic; D009841:Oligonucleotides / Q000627:therapeutic use; D020710:RGS Proteins / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C527276:CXCR4 protein, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; D020710:RGS Proteins; C107413:RGS16 protein; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1