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

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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. © 2014 Cancer Research UK.

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To, S. K. Y., Zeng, W. J., Zeng, J. Z., & Wong, A. S. T. (2014). Hypoxia triggers a Nur77-β-catenin feed-forward loop to promote the invasive growth of colon cancer cells. British Journal of Cancer, 110(4), 935–945. https://doi.org/10.1038/bjc.2013.816

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