Abstract
Loss of von Hippel–Lindau (VHL) protein function can be found in more than 90% of patients with clear cell renal carcinoma (ccRCC). Mice lacking Vhl function in the kidneys have urine concentration defects due to postulated reduction of the hyperosmotic gradient. Hyperosmolality is a kidney-specific microenvironment and induces a unique gene expression pattern. This gene expression pattern is inversely regulated in patients with ccRCC with consequences for cancer-specific survival. Within this study, we tested the hypothesis if Vhl function influences the hyperosmolality induced changes in gene expression. We made use of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 technology to inhibit functional Vhl expression in murine collecting duct cell line. Loss of Vhl function induced morphological changes within the cells similar to epithelial to mesenchymal transition like phenotype. Vhl-deficient cells migrated faster and proliferated slower compared to control cells. Gene expression profiling showed significant changes in gene expression patterns in Vhl-deficient cells compared to control cells. Several genes with unfavorable outcomes showed induced and genes with favorable outcomes for patients with renal cancer reduced gene expression level. Under hyperosmotic condition, the expression of several hyperosmolality induced genes, with favorable prognostic value, was downregulated in cells that do not express functional Vhl. Taken together, this study shows that Vhl interferes with hyperosmotic signaling pathway and hyperosmolality affected pathways might represent new promising targets.
Highlights
Renal cell carcinomas (RCC) are a heterogeneous group of cancers and are among the top 10 cancers worldwide
We have used the murine mpkCCD cells to analyze the role of Vhl in the collecting duct
This cell line has been intensively used to analyze the regulation of Aqp2 and the role of nuclear factor of activated T cells 5 (Nfat5) on hyperosmotic adaptation and they are capable of genetic manipulation [18,19]
Summary
Renal cell carcinomas (RCC) are a heterogeneous group of cancers and are among the top 10 cancers worldwide. RCC arises from renal tubular epithelial cells and more than 80% of all renal neoplasms belong to RCC [1]. The major RCC subtypes are clear cell RCC (ccRCC) with a frequency of around 70–80%, papillary RCC with a frequency of around 10%–15%, and chromophobe RCC with a frequency of around 3–5% [2]. RCC incidence increases with age and is higher for men than women. Risk factors for RCC are, for example, obesity, hypertension, cigarette smoking, chronic kidney disease, hemodialysis, renal transplantation, or acquired kidney cystic disease [3]. Genetic risk factors are involved in the pathogenesis of RCC including the von Hippel–Lindau (VHL) gene, the protein polybromo-1 gene (PBRM-1), and the SET Domain Containing 2 (SETD2) gene [4,5]
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