HIF-1α confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function.
HIF-1α confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function.
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DOI：
10.1158/0008-5472.can-10-2360
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发表时间：
2011-02-15
期刊：
影响因子：
11.2
通讯作者：
Huang LE
中科院分区：
文献类型：
--
作者：
Yoo YG;Christensen J;Huang LE
Hypoxia is known to favor tumor survival and progression. Numerous studies have shown that hypoxia-inducible factor 1α (HIF-1α), an oxygen-sensitive transcription factor, is overexpressed in various types of human cancers and upregulates a battery of hypoxia-responsive genes for the growth and survival of cancer cells. Although tumor progression involves the acquisition of genetic and/or epigenetic changes that confer additional malignant traits, the underlying mechanisms of these changes remain obscure. We recently identified an alternative mechanism of HIF-1α function by which HIF-1α suppresses DNA repair by counteracting c-Myc transcriptional activity that maintains gene expression. Here we demonstrate that this HIF-α–c-Myc pathway plays an essential role in mediating hypoxic effects on malignant progression via genetic alterations, resulting in formation of malignant tumors with aggressive local invasion and epithelial–mesenchymal transition. We show an absolute requirement of the HIF-α–c-Myc pathway for malignant progression, whereas the canonical transcription function of HIF-1α alone is insufficient and seemingly dispensable. This study indicates that HIF-1α induction of genetic alteration is the underlying cause of tumor progression especially by the hypoxic microenvironment.
