title: Hypoxia promotes migration and induces CXCR4 expression via HIF-1α activation in human osteosarcoma.
abstract: BACKGROUND
  Cellular adaptation to a hypoxic microenvironment is essential for tumor progression and is largely mediated by HIF-1α through coordinated regulation of hypoxia-responsive genes. The chemokine SDF-1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers. In this study, we investigated the response of osteosarcoma cells to hypoxia and the expression of CXCR4 and HIF-1α in human osteosarcoma specimens and explored the roles of CXCR4 and HIF-1α in the cell migration process.
  
  
  RESULTS
  We performed immunohistochemistry, immunocytochemistry, quantitative real-time PCR, Western blots and fluorescent reporter assays to evaluate the correlation between CXCR4 and HIF-1α expression in human osteosarcoma specimens or SOSP-9607 cells under normoxic and hypoxic conditions. Transwell assays were used to assess cell migration under different conditions. Exposure of SOSP-9607 cells to hypoxic conditions resulted in significantly increased migration. When SOSP-9607 cells were subjected to hypoxic conditions, the mRNA and protein levels of CXCR4 were significantly increased in a time-dependent manner. Moreover, siHIF-1α significantly decreased the mRNA and protein levels of CXCR4 under hypoxia, whereas pcDNA-HIF-1α significantly increased the mRNA and protein levels of CXCR4 under normoxia. A luciferase reporter gene study showed that siHIF-1α reduced pGL3-CXCR4 luciferase activity. Furthermore, coexpression of HIF-1α and CXCR4 was significantly higher in patients with distant metastasis compared with those without metastasis.
  
  
  CONCLUSIONS
  The hypoxia-HIF-1α-CXCR4 pathway plays a crucial role during the migration of human osteosarcoma cells, and targeting this pathway might represent a novel therapeutic strategy for patients suffering from osteosarcoma.
authors.affiliation: Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Mingjun
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Chengkui
authors.initials: C
authors.lastname: Cai
authors.affiliation: Department of Orthopaedics, Bethune International Peace Hospital, Shijiazhuang, Hebei, People's Republic of China.
authors.forename: Guangyi
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Xiuchun
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Haien
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Liying
authors.initials: L
authors.lastname: Tian
authors.affiliation: Department of Surgery, Xi'an Hospital of TCM, Shaanxi, People's Republic of China.
authors.forename: Xuelian
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Liao
authors.affiliation: Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Baoan
authors.initials: B
authors.lastname: Ma
authors.affiliation: Department of Orthopaedics, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Fan
mesh_terms: D000293:Adolescent; D000328:Adult; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008297:Male; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden; D055815:Young Adult
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4