Deletion of Von Hippel–Lindau Interferes with Hyper Osmolality Induced Gene Expression and Induces an Unfavorable Gene Expression Pattern

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.

Adhesive-Based Fabrication Technique for Culture of Lung Airway Epithelial Cells with Applications in Cell Patterning and Microfluidics

“…Although the method has been well characterized, it lacks consistency due to individual differences in the application of the scratch. New automated wound application technologies and cell culture inserts have been developed to address this, but they do not offer freedom of design. − A standardized method for accurate cell migration studies with customization and user control would be a valuable tool in human airway epithelial cell (HAEC) studies.…”

The Labyrinth of Renal Cell Carcinoma

“…Original articles in this issue show interesting findings with potential clinical application. Examples of the science and research presented in this Special Issue include: the influence of VHL deletion in the expression of an unfavorable genetic pattern in CCRCC [22]; how a low dose of curcumin inhibits RCC's metastatic behavior [23]; the predictive value of the overexpression of EVI1 in CCRCC [24]; the poor outcome of ChRCC patients who lose CDKN1A mRNA and protein expression [25]; the identification of distinct signatures of CCRCC progression through in-depth mapping of urinary N-glycoproteome [26]; how a preclinical evaluation method may evaluate the response to targeted therapies in patients with RCC [27]; the RNA sequencing results obtained in two examples of collecting duct renal cell carcinoma, an aggressive rare variant of RCC [28]; how GSTO1*CC genotype predicts shorter survival in CCRCC male patients [29]; the importance of MTA2 as a biomarker of metastatic progression in RCC [30]; the metabolic reprograming in RCC [31]; the prognostic implications of pAMPK immunostaining and its association with SMAD protein expression in CCRCC [32]; the different amount of chromosomal losses in classic ChRCC compared with the eosinophilic subtype of this neoplasm [33]; the potential influence of circular RNAs in CCRCC prognosis [34]; the association of interleukins 4Rα and 13Rα1 with the progression of RCC [35]; the glutathione metabolism in PRCC [36]; how the profiling of primary and metastatic samples of CCRCC reveals a high homology of metastases with a specific subregion of the primary tumor [37]; the interrelationship between serum uric acid levels and RCC survival [38]; and the importance of ghrelin promoting RCC invasion [39].…”