HIF-1alpha and HIF-2alpha have divergent roles in colon cancer.

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作者：

T Imamura，H Kikuchi，MT Herraiz，DY Park，Daniel C Chung

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摘要：

Hypoxia-inducible factor (HIF)-1 and HIF-2 are heterodimeric transcription factors that mediate the cellular response to hypoxia. Their key regulatory subunits, HIF-1 and HIF-2, are induced similarly by hypoxia, but their functional roles in cancer may be distinct and isoform-specific. SW480 colon cancer cells with stable expression of siRNA to HIF-1 or HIF-2 or both were established. HIF-1-deficient cells displayed lower rates of proliferation and migration, but HIF-2-deficient cells exhibited enhanced anchorage independent growth in a soft agar assay. Xenograft studies revealed that HIF-1 deficiency inhibited overall tumor growth, whereas deficiency of HIF-2 stimulated tumor growth. In human colon cancer tissues, expression of HIF-1 and to a lesser extent, HIF-2, was linked to upregulation of VEGF and tumor angiogenesis. However, loss of expression of HIF-2 but not HIF-1 was strongly correlated with advanced tumor stage. DNA microarray analysis identified distinct sets of HIF-1 and HIF-2 target genes that may explain these phenotypic differences. Collectively, these findings suggest that HIF isoforms may have differing cellular functions in colon cancer. In particular, HIF-1 promoted the growth of SW480 colon cancer cells but HIF-2 appeared to restrain growth. Consequently, therapeutic approaches that target HIF may need to consider these isoform-specific properties. © 2008 Wiley-Liss, Inc.

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关键词：

colon cancer HIF angiogenesis

DOI：

10.1002/ijc.24032

被引量：

287

年份：

2010