title: Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 pathway.
abstract: BACKGROUND
  Environmental and occupational exposure to arsenic is a major public health concern. Although it has been identified as a human carcinogen, the molecular mechanism underlying the arsenic-induced carcinogenesis is not well understood.
  
  
  OBJECTIVE
  We aimed to determine the role and mechanisms of miRNAs in arsenic-induced tumor angiogenesis and tumor growth.
  
  
  METHODS
  We utilized an in vitro model in which human lung epithelial BEAS-2B cells were transformed through long-term exposure to arsenic. A human xenograft tumor model was established to assess tumor angiogenesis and tumor growth in vivo. Tube formation assay and chorioallantoic membranes assay were used to assess tumor angiogenesis.
  
  
  RESULTS
  We found that miR-199a-5p expression levels were more than 100-fold lower in arsenic-transformed cells than parental cells. Re-expression of miR-199a-5p impaired arsenic-induced angiogenesis and tumor growth through its direct targets HIF-1α and COX-2. We further showed that arsenic induced COX-2 expression through HIF-1 regulation at the transcriptional level. In addition, we demonstrated that reactive oxygen species are an upstream event of miR-199a-5p/ HIF-1α/COX-2 pathway in arsenic-induced carcinogenesis.
  
  
  CONCLUSIONS
  The findings establish critical roles of miR-199a-5p and its downstream targets HIF-1/COX-2 in arsenic-induced tumor growth and angiogenesis.
  
  
  BACKGROUND
  He J, Wang M, Jiang Y, Chen Q, Xu S, Xu Q, Jiang BH, Liu LZ. 2014. Chronic arsenic exposure and angiogenesis in human bronchial epithelial cells via the ROS/miR-199a-5p/HIF-1α/COX-2 Pathway. Environ Health Perspect 122:255-261; http://dx.doi.org/10.1289/ehp.1307545.
authors.affiliation: State Key Lab of Reproductive Medicine, Department of Pathology, Nanjing Medical University, Nanjing, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Jiang
authors.forename: Qiudan
authors.initials: Q
authors.lastname: Chen
authors.forename: Shaohua
authors.initials: S
authors.lastname: Xu
authors.forename: Qing
authors.initials: Q
authors.lastname: Xu
authors.forename: Bing-Hua
authors.initials: BH
authors.lastname: Jiang
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Liu
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004781:Environmental Exposure; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; D017382:Reactive Oxygen Species; C531408:mirn199 microRNA, human; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D001151:Arsenic