Format

Send to

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

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

Author information

1
School of Biological Sciences, University of Hong Kong, Pokfulam Road, Hong Kong, China.
2
School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.

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.

PMID:
24423919
PMCID:
PMC3929893
DOI:
10.1038/bjc.2013.816
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center