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

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 r...

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Detalles Bibliográficos
Autores principales: To, S K Y, Zeng, W-J, Zeng, J-Z, Wong, A S T
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929893/
https://www.ncbi.nlm.nih.gov/pubmed/24423919
http://dx.doi.org/10.1038/bjc.2013.816
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author To, S K Y
Zeng, W-J
Zeng, J-Z
Wong, A S T
author_facet To, S K Y
Zeng, W-J
Zeng, J-Z
Wong, A S T
author_sort To, S K Y
collection PubMed
description 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.
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spelling pubmed-39298932015-02-18 Hypoxia triggers a Nur77–β-catenin feed-forward loop to promote the invasive growth of colon cancer cells To, S K Y Zeng, W-J Zeng, J-Z Wong, A S T Br J Cancer Molecular Diagnostics 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. Nature Publishing Group 2014-02-18 2014-01-14 /pmc/articles/PMC3929893/ /pubmed/24423919 http://dx.doi.org/10.1038/bjc.2013.816 Text en Copyright © 2014 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/3.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
spellingShingle Molecular Diagnostics
To, S K Y
Zeng, W-J
Zeng, J-Z
Wong, A S T
Hypoxia triggers a Nur77–β-catenin feed-forward loop to promote the invasive growth of colon cancer cells
title Hypoxia triggers a Nur77–β-catenin feed-forward loop to promote the invasive growth of colon cancer cells
title_full Hypoxia triggers a Nur77–β-catenin feed-forward loop to promote the invasive growth of colon cancer cells
title_fullStr Hypoxia triggers a Nur77–β-catenin feed-forward loop to promote the invasive growth of colon cancer cells
title_full_unstemmed Hypoxia triggers a Nur77–β-catenin feed-forward loop to promote the invasive growth of colon cancer cells
title_short Hypoxia triggers a Nur77–β-catenin feed-forward loop to promote the invasive growth of colon cancer cells
title_sort hypoxia triggers a nur77–β-catenin feed-forward loop to promote the invasive growth of colon cancer cells
topic Molecular Diagnostics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3929893/
https://www.ncbi.nlm.nih.gov/pubmed/24423919
http://dx.doi.org/10.1038/bjc.2013.816
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