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

[beta]-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. Here, we analysed the regulation between Nur77 and [beta]-catenin under hypoxic conditions. Cell proliferation, migration, and invasion assays were performed to assess functional consequences. We showed that hypoxia stimulated co-upregulation of [beta]-catenin and Nur77 in a number of human CRC cell lines. Interestingly, expression of [beta]-catenin and Nur77 by hypoxia formed a mutual feedback regulation circuits that conferred aggressive growth of CRC. Overexpression of [beta]-catenin increased Nur77 transcription through hypoxia-inducible factor-1α rather than T-cell factor. Nur77-mediated activation of [beta]-catenin by hypoxia was independent of both DNA binding and transactivation. Further, we showed that hypoxic activation of [beta]-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 [beta]-catenin and Nur77 expression synergistically stimulated CRC cell migration, invasion, and epithelial-mesenchymal transition. 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.