title: miR-335 inhibits small cell lung cancer bone metastases via IGF-IR and RANKL pathways.
abstract: Small cell lung cancer (SCLC) is a rapidly progressing, incurable cancer that frequently spreads to bone. New insights are needed to identify therapeutic targets to prevent or retard SCLC metastatic progression. Human SCLC SBC-5 cells in mouse xenograft models home to skeletal and nonskeletal sites, whereas human SCLC SBC-3 cells only pervade nonskeletal sites. Because microRNAs (miRNA) often act as tumor regulators, we investigated their role in preclinical models of SCLC. miRNA expression profiling revealed selective and reduced expression of miRNA (miR)-335 and miR-29a in SBC-5 cells, compared with SBC-3 cells. In SBC-5 cells, miR-335 expression correlated with bone osteolytic lesions, whereas miR-29a expression did not. Overexpression of miR-335 in SBC-5 cells significantly reduced cell migration, invasion, proliferation, colony formation, and osteoclast induction in vitro. Importantly, in miR-335 overexpressing SBC-5 cell xenografts (n = 10), there were minimal osteolytic lesions in the majority of mice and none in three mice. Expression of RANK ligand (RANKL) and insulin-like growth factor-I receptor (IGF-IR), key mediators of bone metastases, were elevated in SBC-5 as compared with SBC-3 cells. Mechanistically, overexpression of miR-335 in SBC-5 cells reduced RANKL and IGF-IR expression. In conclusion, loss of miR-335 promoted SCLC metastatic skeletal lesions via deregulation of IGF-IR and RANKL pathways and was associated with metastatic osteolytic skeletal lesions.
  
  
  CONCLUSIONS
  These preclinical findings establish a need to pursue the role of miR-335 in human SCLC with metastatic skeletal disease.
authors: MD, PhD, Laboratory of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Xiang, Chengdu, Sichuan 610041, People's Republic of China. xijieyu@hotmail.com.
authors: Meng
authors: M
authors: Gong
authors: Junrong
authors: J
authors: Ma
authors: Ryan
authors: R
authors: Guillemette
authors: Mingliang
authors: M
authors: Zhou
authors: Yan
authors: Y
authors: Yang
authors: Yujing
authors: Y
authors: Yang
authors: Janet M
authors: JM
authors: Hock
authors: Xijie
authors: X
authors: Yu
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D010010:Osteoclasts; D010014:Osteolysis; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics*; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis / Q000235:genetics*; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000473:pathology*; D014183:Transplantation, Heterologous
chemical_list: C532045:MIRN29a microRNA, human; C556347:MIRN335 microRNA, human; D035683:MicroRNAs; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D017526:Receptor, IGF Type 1