Renal cancer cells lacking hypoxia inducible factor (HIF)-1α expression maintain vascular endothelial growth factor expression through HIF-2α

Toshiaki Shinojima, Mototsugu Oya, Atsushi Takayanagi, Ryuichi Mizuno, Nobuyoshi Shimizu, Masaru Murai

研究成果: Article査読

127 被引用数 (Scopus)

抄録

Recent efforts have been aimed at targeting the hypoxia inducible factor (HIF)-mediated hypoxia-induced gene pathway for renal cell carcinomas (RCC) therapy. Among the various genes induced by HIF, vascular endothelial growth factor (VEGF) is one of the critical mediators in angiogenesis, tumor growth and metastasis. To date, however, limited information is available on the functional differences regarding VEGF transcription between the HIF subunits, namely HIF-1α and HIF-2α. To investigate the HIF-1α and HIF-2α-dependent effect on VEGF gene induction in RCC, a panel of human RCC cell lines was analyzed. We found that a loss of HIF-1α protein expression was a common event in RCC cell lines, which was associated not only with truncated HIF-1α mRNA transcripts but also with transcriptional silencing. Since the CpG rich promoter region of the HIF-1α gene contained a similar frequency of methylated CpG dinucleotides in RCC cell lines, a complex and non-uniform mechanism may be involved in this phenomenon. In these HIF-1α defective cell lines, the knockdown of the HIF-2α gene demonstrated that HIF-2α regulated the VEGF production, irrespective of the VHL gene mutation status. In contrast, HIF-1α played a predominant role in VEGF secretion in the cells expressing both wild-type HIF-1α and HIF-2α proteins. HIF-1α may therefore represent an important target molecule for RCC therapy; however, HIF-2α should be targeted in HIF-1α defective renal cancer cells.

本文言語English
ページ(範囲)529-536
ページ数8
ジャーナルCarcinogenesis
28
3
DOI
出版ステータスPublished - 2007 3月
外部発表はい

ASJC Scopus subject areas

  • 癌研究

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