Mutations in tumor suppressor genes Vhl and Rassf1a cause DNA damage, chromosomal instability and induce gene expression changes characteristic of clear cell renal cell carcinoma.

RASSF1A is frequently biallelically inactivated in clear cell renal cell carcinoma (ccRCC) due to loss of chromosome 3p and promoter hypermethylation. Here we investigated the cellular and molecular consequences of single and combined deletion of the Rassf1a and Vhl tumor suppressor genes to model the common ccRCC genotype of combined loss of function of RASSF1A and VHL. In mouse embryonic fibroblasts and in primary kidney epithelial cells, double deletion of Rassf1a and Vhl caused chromosomal segregation defects and increased formation of micronuclei, demonstrating that pVHL and RASSF1A function to maintain genomic integrity.

Integrated Metabolomic and Transcriptomic Analysis of Modified Nucleosides for Biomarker Discovery in Clear Cell Renal Cell Carcinoma.

Clear cell renal cell carcinoma (ccRCC) accounts for ~75% of kidney cancers. The biallelic inactivation of the von Hippel-Lindau tumor suppressor gene () is the truncal driver mutation of most cases of ccRCC. Cancer cells are metabolically reprogrammed and excrete modified nucleosides in larger amounts due to their increased RNA turnover.

Therapeutic Effects of Inhibition of Sphingosine-1-Phosphate Signaling in HIF-2α Inhibitor-Resistant Clear Cell Renal Cell Carcinoma.

Specific inhibitors of HIF-2α have recently been approved for the treatment of ccRCC in VHL disease patients and have shown encouraging results in clinical trials for metastatic sporadic ccRCC. However, not all patients respond to therapy and pre-clinical and clinical studies indicate that intrinsic as well as acquired resistance mechanisms to HIF-2α inhibitors are likely to represent upcoming clinical challenges. It would be desirable to have additional therapeutic options for the treatment of HIF-2α inhibitor resistant ccRCCs.

HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice.

Mutational inactivation of VHL is the earliest genetic event in the majority of clear cell renal cell carcinomas (ccRCC), leading to accumulation of the HIF-1α and HIF-2α transcription factors. While correlative studies of human ccRCC and functional studies using human ccRCC cell lines have implicated HIF-1α as an inhibitor and HIF-2α as a promoter of aggressive tumour behaviours, their roles in tumour onset have not been functionally addressed. Herein we show using an autochthonous ccRCC model that Hif1a is essential for tumour formation whereas Hif2a deletion has only minor effects on tumour initiation and growth.