PRCC-TFE3 Function and the Role of HIF1a and HIF2a in TFE3-Rearranged Renal Cell Carcinoma Development

PRCC-TFE3 is an oncogenic chimeric transcription factor identified in human TFE3-rearranged renal cell carcinoma. To investigate the function of PRCC-TFE3 in vivo, we generated PRCC-TFE3 knock-in (KI) mice by inserting a loxP-STOP-loxP-PRCC-TFE3 cassette into the Rosa26 locus. When PRCC-TFE3 KI mice were crossed with Cadherin 16-Cre transgenic mice (KSP-Cre), the resulting mice developed TFE3-RCC in the kidney. Our findings revealed that hypoxia-inducible factors HIF1a and HIF2a are directly upregulated by PRCC-TFE3. To clarify the roles of HIF1a and HIF2a in TFE3-RCC development, we further crossed PRCC-TFE3 KI mice with HIF1a flox and/or HIF2a flox mice. Overall design: We performed RNA-seq analysis on kidney samples from Cre(-) control mice, PRCC-TFE3 KI/KSP-Cre mice, PRCC-TFE3 KI/HIF1a flox/KSP-Cre mice, PRCC-TFE3 KI/HIF2a flox/KSP-Cre mice, and PRCC-TFE3 KI/HIF1a/HIF2a flox/KSP-Cre mice.