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Changes of transcriptome in endothelial cells from kidney with tubule-specific conditional Vhlh gene knockout (Hoxb7-Cre-GFP; VhlhloxP/loxP), compared with wild-type.

ABSTRACT: Clear-cell renal cell carcinoma (ccRCC) is the most prevalent histological subtype of RCC in which more than 80% of ccRCC cases are associated with early inactivation of von Hippel-Lindau (VHL) tumor suppressor gene. We have generated a knockout mouse strain in which mouse allele of VHL (Vhlh) is conditionally deleted in the kidney epithelium (cortical tubules, collecting ducts and ascending Loops of Henle). These knockout mice showed high penetrance of inflammation and fibrosis in the kidney in addition to hyperplasia and the appearance of transformed clear cells. These results support the concept of tumor-promoting inflammation. Surprisingly, we found that the expression of pJNK, a marker of inflammation, was expressed in endothelial cells (ECs) in Vhlh mutant tissue although the knockout was in epithelial cells not in endothelial cells. The result indicated the important role of ECs in the initiation tumor progression. Therefore, the aim of this study is to investigate the molecular changes of ECs in the VHL mutant microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE159754 | GEO | 2021/06/18

REPOSITORIES: GEO

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Project description:Patients with loss-of-function mutations of the von Hippel Lindau gene (“VHL-patients”) often develop clear cell renal cell carcinoma (ccRCC). Using archived, formalin-fixed, paraffin-embedded (FFPE) samples and a cohort of eight cases, we sought to determine global proteome alterations that distinguish ccRCC tissue from adjacent, non-malignant kidney tissue in VHL-patients. Our quantitative proteomic analysis clearly discriminated tumor and non-malignant tissue, yielding comparable proteome profiles for the eight ccRCC cases. Limma statistics was used to identify significantly dysregulated proteins in ccRCC. Functional classification of these proteins highlighted a decrease in proteins involved in the tricarboxylic acid cycle and an increase in proteins involved in glycolysis. This profile possibly represents a proteomic fingerprint of the “Warburg effect”, which is a molecular hallmark of ccRCC. Furthermore, we observed an increase in proteins involved in extracellular matrix organization. Of particular note were opposing alterations of Xaa-Pro Aminopeptidases-1 and -2 (XPNPEP-1 and -2): a strong decrease of XPNPEP-2 in ccRCC was accompanied by a strong increase of the related protease XPNPEP-1. In both cases, we corroborated the proteomic results by immunohistochemical analysis of ccRCC and adjacent, non-malignant kidney tissue of VHL patients. To functionally investigate the role of XPNPEP-1 in ccRCC, we performed small-hairpin RNA mediated XPNPEP-1 expression silencing in 786-O ccRCC cells harboring a mutated VHL gene. We found that XPNPEP-1 expression suppresses cellular proliferation and migration. These results suggest that XPNPEP-1 is rather an anti-target in VHL-driven ccRCC. Generally, we present one of the first proteomic profiling studies of ccRCC in VHL patients, comparing normal and tumor tissue, which are both deficient for the VHL tumor suppressor. Methodologically, our work further validates the robustness of using FFPE material for quantitative proteomics.

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Changes of transcriptome in endothelial cells from kidney with tubule-specific conditional Vhlh gene knockout (Hoxb7-Cre-GFP; VhlhloxP/loxP), compared with wild-type.

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