Abstract
Stabilization of the hypoxia-inducible factor-1α (HIF-1α) transcription complex, caused by intratumoural hypoxia, promotes tumour progression and metastasis, leading to treatment failure and mortality in different types of human cancers. The transcription factor TWIST is a master regulator of gastrulation and mesoderm-specification and was implicated recently as an essential mediator of cancer metastasis. Notably, HIF-1α- and TWIST-null mice show similarities in their phenotypes. Here, we have shown that hypoxia or overexpression of HIF-1α promotes epithelial–mesenchymal transition (EMT) and metastastic phenotypes. We also found that HIF-1 regulates the expression of TWIST by binding directly to the hypoxia-response element (HRE) in the TWIST proximal promoter. However, siRNA-mediated repression of TWIST in HIF-1α-overexpressing or hypoxic cells reversed EMT and metastastic phenotypes. Co-expression of HIF-1α, TWIST and Snail in primary tumours of patients with head and neck cancers correlated with metastasis and the worst prognosis. These results provide evidence of a key signalling pathway involving HIF-1α and TWIST that promotes metastasis in response to intratumoural hypoxia.
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Acknowledgements
We thank K. W. Chang for TMA construction, and C. H. Huang and D. H. Hsu for excellent technical assistance. We are grateful to T. Y. Chou and W. Y. Li for providing expert opinions on pathology reading and immunohistochemical analysis. This work was supported in part by National Research Program for Genomic Medicine (DOH-96-TD-G-111-002)(K.J.W.), Taipei Veterans General Hospital VGH 96-C1-126, V-96-ER2-008 (M.H.Y.), V-96-ER2-009 (S.Y.C.), National Science Council (NSC-95-2320-B-010-065)(K.J.W.); (95-2314-B-075-083)(M.H.Y.), a grant from Ministry of Education, Aim for the Top University Plan (95A-C-D01-PPG-05, 96A-D-D139)(K.J.W.), and National Health Research Institutes (NHRI-EX-96-9611BI)(K.J.W.).
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K. J. W., M. H. Y. and M. Z. W. conceived and designed the experiments; M. H. Y. and M. Z. W. performed the experiments with the assistance of S. H. C. for in vivo work; M. H. Y., M. Z. W., S. C. T. and K. J. W. analysed the data; K. J. W. and M. H. Y. wrote the paper with the assistance of S. C. T; S. Y. C., C. J. L., P. M. C. and M. H. Y. collected and treated samples from head and neck cancer patients.
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Supplementary figures S1, S2, S3, S4, S5, S6, Supplementary tables S1, S2, S3, S4, S5, S6 and Supplementary Methods (PDF 1824 kb)
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Yang, MH., Wu, MZ., Chiou, SH. et al. Direct regulation of TWIST by HIF-1α promotes metastasis. Nat Cell Biol 10, 295–305 (2008). https://doi.org/10.1038/ncb1691
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DOI: https://doi.org/10.1038/ncb1691