title: Hypoxia triggers a Nur77-β-catenin feed-forward loop to promote the invasive growth of colon cancer cells.
abstract: BACKGROUND
  β-Catenin is a potent oncogenic protein in colorectal cancer (CRC), but the targets and regulation of this important signalling molecule are not completely understood. Hypoxia is a prominent feature of solid tumours that contributes to cancer progression.
  
  
  METHODS
  Here, we analysed the regulation between Nur77 and β-catenin under hypoxic conditions. Cell proliferation, migration, and invasion assays were performed to assess functional consequences.
  
  
  RESULTS
  We showed that hypoxia stimulated co-upregulation of β-catenin and Nur77 in a number of human CRC cell lines. Interestingly, expression of β-catenin and Nur77 by hypoxia formed a mutual feedback regulation circuits that conferred aggressive growth of CRC. Overexpression of β-catenin increased Nur77 transcription through hypoxia-inducible factor-1α rather than T-cell factor. Nur77-mediated activation of β-catenin by hypoxia was independent of both DNA binding and transactivation. Further, we showed that hypoxic activation of β-catenin was independent of the classical adenomatous polyposis coli and p53 pathways, but stimulated by phosphatidylinositol 3-kinase/Akt in a Nur77-dependent manner. Under hypoxic conditions, enhanced β-catenin and Nur77 expression synergistically stimulated CRC cell migration, invasion, and epithelial-mesenchymal transition.
  
  
  CONCLUSIONS
  These findings provide a novel molecular mechanism for hypoxic CRCs that may contribute to tumour progression, and its targeting may represent an effective therapeutic avenue.
authors.affiliation: School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong, China.
authors.forename: S K Y
authors.initials: SK
authors.lastname: To
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
authors.forename: W-J
authors.initials: WJ
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.
authors.forename: J-Z
authors.initials: JZ
authors.lastname: Zeng
authors.affiliation: School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong, China.
authors.forename: A S T
authors.initials: AS
authors.lastname: Wong
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt