Hypoxia triggers a Nur77-β-catenin feed-forward loop to promote the invasive growth of colon cancer cells

Br J Cancer. 2014 Feb 18;110(4):935-45. doi: 10.1038/bjc.2013.816. Epub 2014 Jan 14.

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / metabolism
  • Cell Hypoxia / physiology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Colonic Neoplasms / pathology*
  • DNA-Binding Proteins / metabolism
  • Epithelial-Mesenchymal Transition
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HEK293 Cells
  • HT29 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Neoplasm Invasiveness
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • RNA, Small Interfering
  • Signal Transduction
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NR4A1 protein, human
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • RNA, Small Interfering
  • Tumor Suppressor Protein p53
  • beta Catenin
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt