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Updated: Aug 15, 2026
Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
Published on: February 8, 2020
Dual loss of VHL and RASSF1A enhances tumorigenicity in clear cell renal cancer
Howard Donninger1, Rachel Ferrill2, Katherine Hobbing2
1Brown Cancer Center, Department of Medicine, University of Louisville, Louisville, KY, United States.
Introduction:
Clear Cell Renal cell carcinoma (ccRCC) is the most common form of kidney cancer. The VHL tumor suppressor is lost or mutated in the majority of ccRCC and hereditary mutations in VHL predispose patients to ccRCC. However, another tumor suppressor, RASSF1A is inactivated at even higher levels in ccRCC. The majority of ccRCC lose function of both proteins. This suggests there may be some functional link between them. We found that the RASSF1A and VHL proteins can form a complex, suggesting they may act in concert to suppress the tumorigenic phenotype.
Methods:
We generated two matched sets of Renal cancer tumor cell systems where we added back or knocked down both genes. We also made compound transgenic mice with induced, dual inactivation.
Results:
In the add-back system we found that the proteins cooperated to suppress 3D cell growth and sensitized cells to apoptosis inducing agents. In the knockdown system, we found the double loss cooperated to promote growth in 3D. In cell line xenografts, we found that the loss of VHL alone was insufficient to promote tumorigenesis, but it acted as an accelerant on tumor growth by RASSF1A deficient cells, which showed enhanced vascularization differential deregulation of HIF1α compared to HIF2α.
Discussion:
This is the first report of an interaction between RASSF1A and VHL and may explain why RASSF1A is so frequently inactivated in Renal cancer. However, further studies in transgenic mice showed that dual inactivation of the tumor suppressors did not result in the formation of tumors or macrocysts. Thus, additional genetic lesions are likely required for the development of ccRCC.
Insights
Clear Cell Renal Cell Carcinoma (ccRCC) involves the loss of VHL and RASSF1A tumor suppressors. These proteins interact and cooperate to suppress tumor growth, but additional genetic changes are needed for ccRCC development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clear Cell Renal Cell Carcinoma (ccRCC) is the most common kidney cancer.
- Loss or mutation of the VHL tumor suppressor is common in ccRCC.
- RASSF1A is inactivated at high frequency in ccRCC, suggesting a functional link with VHL.
Purpose of the Study:
- To investigate the functional relationship between RASSF1A and VHL in ccRCC.
- To determine if RASSF1A and VHL proteins interact and cooperate in tumor suppression.
Main Methods:
- Generated matched renal cancer cell systems with gene add-back or knockdown for RASSF1A and VHL.
- Created compound transgenic mice with induced dual inactivation of RASSF1A and VHL.
- Assessed tumor cell growth, apoptosis sensitivity, and xenograft tumor development.
Main Results:
- RASSF1A and VHL proteins form a complex, cooperating to suppress 3D cell growth and sensitize cells to apoptosis.
- Loss of both RASSF1A and VHL promotes 3D cell growth.
- Loss of VHL alone did not promote tumorigenesis but accelerated tumor growth in RASSF1A-deficient cells, with altered vascularization and HIF1α/HIF2α deregulation.
Conclusions:
- This study reports the first interaction between RASSF1A and VHL, potentially explaining RASSF1A's frequent inactivation in renal cancer.
- Dual inactivation of RASSF1A and VHL alone is insufficient for ccRCC development, indicating the necessity of additional genetic lesions.
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