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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

01-12-2021 | Kidney Cancer | Research

Loss of RANBP3L leads to transformation of renal epithelial cells towards a renal clear cell carcinoma like phenotype

Authors: Dmitry Chernyakov, Alexander Groß, Annika Fischer, Nicola Bornkessel, Christoph Schultheiss, Dennis Gerloff, Bayram Edemir

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

Background

Renal cell carcinomas (RCC) are characterized by the deregulation of several hundred hyperosmolality-responsive genes. High expression of a subset of these genes including the Ran binding protein 3 like (RANBP3L) is linked to a favorable prognostic outcome in RCC. However, the cellular function of RANBP3L remains largely unknown.

Methods

We used CRISPR/Cas9-mediated gene editing to generate functional deletions of the Ranbp3l and nuclear factor of activated T cells 5 (Nfat5) gene loci in a murine renal cell line. The NFAT5-KO cells were used to assess the regulation of Ranbp3l by NFAT5 using immunofluorescence, RNA-Seq and promoter assays. RANBP3L-deficient cells were analyzed for changes in cell morphology, proliferation, migration and colony-forming capacity using immunofluorescence and live cell imaging. RANPB3L-dependent changes in gene expression were identified by RNA-Seq.

Results

We show that NFAT5 directly regulates Ranpb3l under hyperosmotic conditions by binding its promoter. Functional analysis of RANBP3L-deficient cells revealed a loss of epithelial structure, an increased cell migration behavior and colony forming capacity, accompanied by massive alterations in gene expression, all of which are hallmarks for tumor cells. Strikingly, a RANBP3L dependent signature of 60 genes separated samples with clear cell carcinoma (KIRC) from papillary (KIRP), chromophobe renal carcinoma (KICH) and healthy tissue.

Conclusions

Loss of RANBP3L induces a tumor like phenotype resembles RCC, especially KIRC, on the morphological and gene expression level and might promote tumor development and progression. Therapeutic reconstitution or elevation of osmoregulated RANBP3L expression might represent a novel treatment strategy for RCC or KIRC.
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Metadata
Title
Loss of RANBP3L leads to transformation of renal epithelial cells towards a renal clear cell carcinoma like phenotype
Authors
Dmitry Chernyakov
Alexander Groß
Annika Fischer
Nicola Bornkessel
Christoph Schultheiss
Dennis Gerloff
Bayram Edemir
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-01982-y

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