title: Hypoxia induces epithelial-mesenchymal transition via activation of SNAI1 by hypoxia-inducible factor -1α in hepatocellular carcinoma.
abstract: BACKGROUND
  High invasion and metastasis are the primary factors causing poor prognosis of patients with hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying these biological behaviors have not been completely elucidated. In this study, we investigate the molecular mechanism by which hypoxia promotes HCC invasion and metastasis through inducing epithelial-mesenchymal transition (EMT).
  
  
  METHODS
  The expression of EMT markers was analyzed by immunohistochemistry. Effect of hypoxia on induction of EMT and ability of cell migration and invasion were performed. Luciferase reporter system was used for evaluation of Snail regulation by hypoxia-inducible factor -1α (HIF-1α).
  
  
  RESULTS
  We found that overexpression of HIF-1α was observed in HCC liver tissues and was related to poor prognosis of HCC patients. HIF-1α expression profile was correlated with the expression levels of SNAI1, E-cadherin, N-cadherin and Vimentin. Hypoxia was able to induce EMT and enhance ability of invasion and migration in HCC cells. The same phenomena were also observed in CoCl2-treated cells. The shRNA-mediated HIF-1α suppression abrogated CoCl2-induced EMT and reduced ability of migration and invasion in HCC cells. Luciferase assay showed that HIF-1α transcriptional regulated the expression of SNAI1 based on two hypoxia response elements (HREs) in SNAI1 promoter.
  
  
  CONCLUSIONS
  We demonstrated that hypoxia-stabilized HIF1α promoted EMT through increasing SNAI1 transcription in HCC cells. This data provided a potential therapeutic target for HCC treatment.
authors.affiliation: Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Li
authors.forename: Yujun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Junjie
authors.initials: J
authors.lastname: Shen
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Qingliang
authors.initials: Q
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Feng
authors.forename: Jiahong
authors.initials: J
authors.lastname: Dong
authors.forename: Cheng
authors.initials: C
authors.lastname: Qian
mesh_terms: D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D003035:Cobalt / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000235:genetics*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D011379:Prognosis; D055550:Protein Stability / Q000187:drug effects; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014746:Vimentin / Q000378:metabolism
chemical_list: D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D003035:Cobalt; C018021:cobaltous chloride