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Updated: Mar 18, 2026
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
CRISPR-Mediated VHL Knockout Generates an Improved Model for Metastatic Renal Cell Carcinoma
Shiruyeh Schokrpur1, Junhui Hu1,2,3, Diana L Moughon1
1Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California at Los Angeles CA 90095, USA.
Abstract:
Metastatic renal cell carcinoma (mRCC) is nearly incurable and accounts for most of the mortality associated with RCC. Von Hippel Lindau (VHL) is a tumour suppressor that is lost in the majority of clear cell RCC (ccRCC) cases. Its role in regulating hypoxia-inducible factors-1α (HIF-1α) and -2α (HIF-2α) is well-studied. Recent work has demonstrated that VHL knock down induces an epithelial-mesenchymal transition (EMT) phenotype. In this study we showed that a CRISPR/Cas9-mediated knock out of VHL in the RENCA model leads to morphologic and molecular changes indicative of EMT, which in turn drives increased metastasis to the lungs. RENCA cells deficient in HIF-1α failed to undergo EMT changes upon VHL knockout. RNA-seq revealed several HIF-1α-regulated genes that are upregulated in our VHL knockout cells and whose overexpression signifies an aggressive form of ccRCC in the cancer genome atlas (TCGA) database. Independent validation in a new clinical dataset confirms the upregulation of these genes in ccRCC samples compared to adjacent normal tissue. Our findings indicate that loss of VHL could be driving tumour cell dissemination through stabilization of HIF-1α in RCC. A better understanding of the mechanisms involved in this phenomenon can guide the search for more effective treatments to combat mRCC.
Insights
Loss of the Von Hippel Lindau (VHL) tumor suppressor in renal cell carcinoma promotes metastasis through epithelial-mesenchymal transition (EMT) driven by HIF-1α. This discovery offers new therapeutic targets for metastatic RCC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic renal cell carcinoma (mRCC) presents a significant clinical challenge with limited curative options.
- The Von Hippel Lindau (VHL) tumor suppressor gene is frequently inactivated in clear cell RCC (ccRCC).
- VHL's role in regulating hypoxia-inducible factors (HIFs) is established, and its loss is linked to epithelial-mesenchymal transition (EMT).
Purpose of the Study:
- To investigate the role of VHL loss in driving ccRCC metastasis.
- To elucidate the molecular mechanisms, particularly the involvement of HIF-1α, in VHL-deficient ccRCC.
- To identify potential therapeutic targets for mRCC based on VHL-HIF-1α pathway alterations.
Main Methods:
- CRISPR/Cas9-mediated VHL knockout in the RENCA mouse model.
- Assessment of morphologic and molecular changes indicative of EMT.
- RNA sequencing (RNA-seq) to identify differentially expressed genes.
- Analysis of The Cancer Genome Atlas (TCGA) and clinical datasets for gene validation.
Main Results:
- VHL knockout in RENCA cells induced EMT and increased lung metastasis.
- HIF-1α deficiency prevented EMT changes following VHL knockout.
- RNA-seq identified several HIF-1α-regulated genes upregulated in VHL-null cells, correlating with aggressive ccRCC.
- Independent validation confirmed the upregulation of these genes in clinical ccRCC samples.
Conclusions:
- Loss of VHL promotes ccRCC metastasis via HIF-1α stabilization and subsequent EMT.
- The identified HIF-1α-regulated genes represent potential biomarkers for aggressive ccRCC.
- Understanding this VHL-HIF-1α-EMT axis is crucial for developing novel mRCC treatments.
