摘要
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.
原文 | 英語 |
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頁(從 - 到) | 295-305 |
頁數 | 11 |
期刊 | Nature Cell Biology |
卷 | 10 |
發行號 | 3 |
DOIs | |
出版狀態 | 已出版 - 03 2008 |
對外發佈 | 是 |