Abstract
A common feature of tumorigenesis is the upregulation of angiogenesis pathways in order to supply nutrients via the blood for the growing tumor. Understanding how cells promote angiogenesis and how to control these processes pharmaceutically are of great clinical interest. Clear cell renal cell carcinoma (ccRCC) is the most common form of sporadic and inherited kidney cancer which is associated with excess neovascularization. ccRCC is highly associated with biallelic mutations in the von Hippel–Lindau (VHL) tumor suppressor gene. Although upregulation of the miR-212/132 family and disturbed VHL signaling have both been linked with angiogenesis, no evidence of a possible connection between the two has yet been made. We show that miRNA-212/132 levels are increased after loss of functional pVHL, the protein product of the VHL gene, in vivo and in vitro. Furthermore, we show that blocking miRNA-212/132 with anti-miRs can significantly alleviate the excessive vascular branching phenotype characteristic of vhl−/− mutant zebrafish. Moreover, using human umbilical vascular endothelial cells (HUVECs) and an endothelial cell/pericyte coculture system, we observed that VHL knockdown promotes endothelial cells neovascularization capacity in vitro, an effect which can be inhibited by anti-miR-212/132 treatment. Taken together, our results demonstrate an important role for miRNA-212/132 in angiogenesis induced by loss of VHL. Intriguingly, this also presents a possibility for the pharmaceutical manipulation of angiogenesis by modulating levels of MiR212/132.
Highlights
Clear cell renal cell carcinoma, the most common form of sporadic and inherited kidney cancer, is highly associated with mutations in the von Hippel-Lindau (VHL) gene [1,2].The protein product of the von Hippel–Lindau (VHL) gene is an E3 ubiquitin ligase involved in the degradation of hypoxia-inducible transcription factor subunits (HIF1α)
In this study, using a combination of cellular models, patient Clear cell renal cell carcinoma (ccRCC) material with biallelic loss of VHL and a previously described vhl−/− mutant zebrafish model, we show that miR-212/132 is upregulated after VHL knockdown or mutation and that this upregulation is at least partially responsible for pro-angiogenic effects
VHL mutations proven by sequencing (Figure 1E). These results demonstrate that miR-132 is increased proven by sequencing (Figure 1E). These results demonstrate that miR-132 is increased in response in response to the pseudo-hypoxia induced the of lack of functional eventually to the pseudo-hypoxia induced by thebylack functional product of the VHL gene (pVHL),pVHL, which which eventually leads toleads to overexpression of miR-132
Summary
The protein product of the VHL gene (pVHL) is an E3 ubiquitin ligase involved in the degradation of hypoxia-inducible transcription factor subunits (HIF1α). People born with a mutation in one VHL allele may acquire somatic mutations in the second allele, resulting in consequent angiogenic symptoms and a variety of tumors, including ccRCC [3]. Another hallmark of ccRCC is the activated phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3k)/AKT pathway signaling, higher levels of which is significantly correlated with a worse survival rate [2], the mechanism by which this occurs is still not fully understood
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