Abstract
Background: von Hippel–Lindau (VHL) inactivation is common in sporadic clear cell renal cell carcinomas (ccRCC). pVHL is part of the ubiquitin ligase complex that targets the alpha subunits of hypoxia-inducible transcription factor (HIF) for degradation under well-oxygenated conditions. In the absence of wild-type pVHL, as observed in VHL patients and most sporadic ccRCCs, constitutive upregulation of HIF results in transcriptional activation of angiogenesis-related genes, such as VEGF. Differences in angiogenic activity within the group of ccRCCs were reported and strong genotype-phenotype correlations were found in patients with VHL disease, raising a question about the importance of VHL inactivation status in angiogenic behaviour and tumour progression.Methods: To address this question, we investigated the influence of VHL mutation (direct sequencing)/hypermethylation (methylation-specific PCR) on angiogenesis/tumour parameters (immunohistochemistry) in 150 patients with sporadic ccRCC.Results: We found no significant association between VHL mutation or methylation and angiogenesis/tumour parameters.Conclusions: These data indicate that tumour progression and angiogenesis are not directly influenced by VHL alterations and that additional genetic/epigenetic events should be considered to explain the diverse angiogenic and proliferative behaviour during tumour progression.
Highlights
The most widely observed genetic aberration in clear cell RCC is loss of chromosome 3p, harbouring the von Hippel–Lindau (VHL) tumour suppressor gene, which is located on chromosome 3p25 and plays an important role in hereditary and sporadic clear cell renal cell carcinomas (ccRCC) [1]. 50–75% of sporadic ccRCCs show biallelic VHL inactivation [1–3]
The VHL gene exists of three exons and VHL mutations are heterogeneous distributed throughout the coding sequence, except that intragenic missense mutations are rarely seen within the first 50 codons [4]
It can be hypothesized that a difference in angiogenesis/hypoxia can be expected in ccRCC patients with versus without functional VHL
Summary
The most widely observed genetic aberration in clear cell RCC (ccRCC) is loss of chromosome 3p, harbouring the von Hippel–Lindau (VHL) tumour suppressor gene, which is located on chromosome 3p25 and plays an important role in hereditary and sporadic ccRCC [1]. 50–75% of sporadic ccRCCs show biallelic VHL inactivation [1–3]. The most widely observed genetic aberration in clear cell RCC (ccRCC) is loss of chromosome 3p, harbouring the von Hippel–Lindau (VHL) tumour suppressor gene, which is located on chromosome 3p25 and plays an important role in hereditary and sporadic ccRCC [1]. The best characterized function of pVHL is its role as a component of the ubiquitin E3 ligase complex that targets hypoxia inducible factor HIFα for ubiquitin-dependent proteasome degradation [9, 10]. The α-subunits of HIF are rapidly degraded by the proteasome under normal conditions, but are stabilized by hypoxia [11]. In hypoxic cells and in RCC, lacking functional pVHL, HIF-α degradation is suppressed, leading to enhanced transcription of target genes, including genes involved in cell proliferation, apoptosis, extracellular matrix formation, energy metabolism and pro-angiogenic genes such as vascular endothelial growth factor (VEGF) contributing to the activation of the angiogenic switch [1,12–15]. It can be hypothesized that a difference in angiogenesis/hypoxia can be expected in ccRCC patients with versus without functional VHL
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