title: Hypoxia-inducible microRNA-488 regulates apoptosis by targeting Bim in osteosarcoma.
abstract: BACKGROUND
  Osteosarcoma is a malignant bone cancer of which the survival rate is still low. One reason for this low survival rate is drug resistance. In the past, it has been shown that microRNAs may play critical roles in osteosarcoma development and drug resistance. The mechanisms by which osteosarcoma cells acquire this resistance have, however, remained largely unknown. Here, we aimed at assessing the role of microRNA-488 in the acquisition of drug resistance by osteosarcoma cells.
  
  
  METHODS
  Quantitative RT-PCR was used to measure the expression of microRNA-488 in primary osteosarcoma samples and in osteosarcoma-derived cells, whereas microRNA-488 mimics and inhibitors were used to modify its expression in these cells. Luciferase reporter, Western blotting, cell viability, apoptosis and ChIP assays were used to assess the various effects of modified microRNA-488 expression in osteosarcoma-derived cells.
  
  
  RESULTS
  We found that microRNA-488 is over-expressed in primary osteosarcoma tissues and osteosarcoma-derived cells and that hypoxia can induce microRNA-488 expression via binding to the hypoxia response element (HRE) in its promoter. We also found that exogenous over-expression of microRNA-488 promotes the proliferation, reduces the apoptosis and decreases the sensitivity to chemotherapy (doxorubicin) of osteosarcoma cells via direct targeting of the tumor suppressor Bim, which is a mediator of apoptosis. In contrast, we found that transfection of a microRNA-488 inhibitor resulted in an increase in both apoptosis and drug sensitivity, and a decrease in proliferation.
  
  
  CONCLUSIONS
  Our data suggest that miRNA-488 may serve as a predictor of response to chemotherapy and as a therapeutic target in human osteosarcomas.
authors.affiliation: Department of Bone, Zhujiang Hospital, Southern Medical University, Guangdong Province, Guangzhou, China.
authors.forename: Chusong
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Department of Bone, The Third People Hospital, Guangdong Province, Huizhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Tan
authors.affiliation: Department of Bone, Zhujiang Hospital, Southern Medical University, Guangdong Province, Guangzhou, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Lv
authors.affiliation: Department of Bone, Donghua Hospital, Guangdong Province, Dongguan, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Bone, The Third People Hospital, Guangdong Province, Huizhou, China. jinsun365@163.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D000072224:Bcl-2-Like Protein 11; C561403:MIRN488 microRNA, human; D035683:MicroRNAs
keywords: Apoptosis; Bim; Drug resistance; Osteosarcoma; microRNA-488