title: MicroRNA-33a functions as a bone metastasis suppressor in lung cancer by targeting parathyroid hormone related protein.
abstract: BACKGROUND
  Bone is a common site of metastasis for lung cancer, and is associated with significant morbidity and a dismal prognosis. MicroRNAs (miRNAs) are increasingly implicated in regulating the progression of malignancies.
  
  
  METHODS
  The efficacy of miR-33a or anti-miR-33a plasmid was assessed by Real-time PCR. Luciferase assays were using One-Glo Luciferase Assay System. Measurement of secreted factors was determined by ELISA kit.
  
  
  RESULTS
  We have found that miR-33a, which is downregulated in lung cancer cells, directly targets PTHrP (parathyroid hormone-related protein), a potent stimulator of osteoclastic bone resorption, leading to decreased osteolytic bone metastasis. We also found that miR-33a levels are inversely correlated with PTHrP expression between human normal bronchial cell line and lung cancer cell lines. The reintroduction of miR-33a reduces the stimulatory effect of A549 on the production of osteoclastogenesis activator RANKL (receptor activator of nuclear factor kappa-B ligand) and M-CSF (macrophage colony-stimulating factor) on osteoblasts, while the expression of PTHrP is decreased in A549 cells. miR-33a overexpression also reduces the inhibitory activity of A549 on the production of OPG (osteoprotegerin), an osteoclastogenesis inhibitor. In addition, miR-33a-mediated PTHrP downregulation results in decreased IL-8 secretion in A549, which contributes to decreased lung cancer-mediated osteoclast differentiation and bone resorption.
  
  
  CONCLUSIONS
  These findings have led us to conclude that miR-33a may be a potent tumor suppressor, which inhibits direct and indirect osteoclastogenesis through repression of PTHrP.
  
  
  CONCLUSIONS
  miR-33a may even predict a poor prognosis for lung cancer patients.
authors: Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Po-Lin
authors: PL
authors: Kuo
authors: Szi-Hui
authors: SH
authors: Liao
authors: Jen-Yu
authors: JY
authors: Hung
authors: Ming-Shyan
authors: MS
authors: Huang
authors: Ya-Ling
authors: YL
authors: Hsu
mesh_terms: D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000096:biosynthesis / Q000235:genetics; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis* / Q000235:genetics; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; C550416:MIRN33a microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D053245:RANK Ligand; D012334:RNA, Neoplasm; C505688:TNFSF11 protein, human