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Direct regulation of TWIST by HIF-1α promotes metastasis

Nature Cell Biology volume 10, pages 295305 (2008) | Download Citation

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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.).

Author information

Author notes

    • Muh-Hwa Yang
    •  & Min-Zu Wu

    These authors contributed equally to this work.

Affiliations

  1. Institutes of Biochemistry & Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Li-Niong Street, Peitou, Taipei 112, Taiwan.

    • Muh-Hwa Yang
    • , Min-Zu Wu
    •  & Kou-Juey Wu
  2. Clinical Medicine, National Yang-Ming University, No. 155, Sec. 2, Li-Niong Street, Peitou, Taipei 112, Taiwan.

    • Muh-Hwa Yang
    • , Shih-Hwa Chiou
    •  & Kou-Juey Wu
  3. Division of Hematology-Oncology, Departments of Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan.

    • Muh-Hwa Yang
    •  & Po-Min Chen
  4. Medical Research & Education, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan.

    • Shih-Hwa Chiou
  5. Otolaryngology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan.

    • Shyue-Yih Chang
  6. Genomic Research Center, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei 112, Taiwan.

    • Muh-Hwa Yang
    • , Po-Min Chen
    • , Shyue-Yih Chang
    •  & Kou-Juey Wu
  7. Department of Dentistry, Taipei Mackay Memorial Hospital, No. 92, Sec. 2, Chung-Shan North Road, Taipei 104, Taiwan.

    • Chung-Ji Liu
  8. Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No. 1, Sec, 2, Jen-Ai Road, Taipei 100, Taiwan.

    • Shu-Chun Teng

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Contributions

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.

Corresponding author

Correspondence to Kou-Juey Wu.

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    Supplementary Information

    Supplementary figures S1, S2, S3, S4, S5, S6, Supplementary tables S1, S2, S3, S4, S5, S6 and Supplementary Methods

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DOI

https://doi.org/10.1038/ncb1691

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