Genome-Wide Profiling of TRACK Kidneys Shows Similarity to the Human ccRCC Transcriptome.

Unlabelled: Renal cell carcinoma (RCC) is the most common cancer arising from the kidney in adults, with clear cell RCC (ccRCC) representing the majority of all RCCs. Expression of a human HIF1α triple-mutant (P402A, P564A, and N803A) construct in the proximal tubule cells of C57BL/6 mice [TRAnsgenic model of Cancer of the Kidney (TRACK); ref. 1] mimics the histologic changes found in early stage human ccRCC. To better understand the genomic landscape, a high-throughput sequence analysis was performed with cDNA libraries (RNAseq) derived from TRACK transgenic positive (TG(+)) kidney cortex along with human ccRCC transcripts from the Oncomine and The Cancer Genome Atlas databases. Importantly, the expression profiles of TRACK TG(+) kidneys show significant similarities with those observed in human ccRCC, including increased expression of genes involved in glycolysis and the tricarboxylic acid cycle. Some of the transcripts overexpressed in both the TRACK mouse model and human ccRCC include ANKRD37, CA9, EGLN3, HK2, NDUFA4L2, and SLC16A3. These data suggest that constitutive activation of HIF1α in kidney proximal tubule cells transcriptionally reprograms the regulation of metabolic pathways in the kidney and that HIF1α is a major contributor to the altered metabolism observed in human ccRCC.

Implications: TRACK (GGT-HIF1αM3) kidney mRNA profiles show similarities to human ccRCC transcriptome and phenotypes associated with the Warburg effect.