Hypoxia responsiveness in renal cell carcinoma

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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. VHL gene was inactivated in 4 of 9 cell lines, due to frame shift mutation or hypermethylation. All four cell lines with VHL gene activation had either a truncated or defective HIF-1α expression. Transcriptional silencing, accompanying aberrant CpG island promotor region methylation or truncated mRNA expression was observed in 5 of 9 cell lines which resulted in the absence of wild type HIF-1α protein expression. The reduced potein expression was due to a low level of mRNA expression. Therefore, as a whole, protein expression was correlated with mRNA expression. In the cell lines devoid of HIF-1α expression, VEGF expression was maintained by HIF-2α expression. Indeed, 769P cell lacking both HIF-1α and HIF-2α had low VEGF expression. 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. The transcriptional silencing or truncated mRNA expression of HIF-1α was a common phenomenon in human RCC cell lines. 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.