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BMC Medicine
Published in: BMC Medicine 1/2010

Open Access 01-12-2010 | Research article

The VHL-dependent regulation of microRNAs in renal cancer

Authors: Calida S Neal, Michael Z Michael, Lesley H Rawlings, Mark B Van der Hoek, Jonathan M Gleadle

Published in: BMC Medicine | Issue 1/2010

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Abstract

Background

The commonest histological type of renal cancer, clear cell renal cell carcinoma (cc RCC), is associated with genetic and epigenetic changes in the von Hippel-Lindau (VHL) tumour suppressor. VHL inactivation leads to induction of hypoxia-inducible factors (HIFs) and a hypoxic pattern of gene expression. Differential levels of specific microRNAs (miRNAs) are observed in several tumours when compared to normal tissue. Given the central role of VHL in renal cancer formation, we examined the VHL-dependent regulation of miRNAs in renal cancer.

Methods

VHL-dependent miRNA expression in cc RCC was determined by microarray analysis of renal cell line RCC4 with mutated VHL (RCC4-VHL) and reintroduced wild-type VHL (RCC4 + VHL). Five miRNAs highly upregulated in RCC4 + VHL and five miRNAs highly downregulated in RCC4 + VHL were studied further, in addition to miR-210, which is regulated by the HIF-VHL system. miRNA expression was also measured in 31 cc RCC tumours compared to adjacent normal tissue.

Results

A significant increase in miR-210, miR-155 and miR-21 expression was observed in the tumour tissue. miR-210 levels also showed a correlation with a HIF-regulated mRNA, carbonic anhydrase IX (CAIX), and with VHL mutation or promoter methylation. An inverse correlation was observed between miR-210 expression and patient survival, and a putative target of miR-210, iron-sulfur cluster assembly protein (ISCU1/2), shows reciprocal levels of mRNA expression in the tumours.

Conclusions

We have identified VHL-regulated miRNAs and found that for some the regulation is HIF-dependent and for others it is HIF-independent. This pattern of regulation was also seen in renal cancer tissue for several of these miRNAs (miR-210, miR-155, let-7i and members of the miR-17-92 cluster) when compared with normal tissue. miR-210 showed marked increases in expression in renal cancer and levels correlated with patient survival. The inverse correlation between miR-210 levels and ISCU1/2 provides support for the hypothesis that ISCU1/2 is a target of miR-210 and that it may contribute to the anaerobic respiration seen in renal (and other) tumours.
See Commentary: http://​www.​biomedcentral.​com/​1741-7015/​8/​65
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Metadata
Title
The VHL-dependent regulation of microRNAs in renal cancer
Authors
Calida S Neal
Michael Z Michael
Lesley H Rawlings
Mark B Van der Hoek
Jonathan M Gleadle
Publication date
01-12-2010
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2010
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/1741-7015-8-64

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