Analyses of the Transcriptome and Metabolome Demonstrate That HIF1α Mediates Altered Tumor Metabolism in Clear Cell Renal Cell Carcinoma

Hypoxia inducible factor 1 alpha (HIF1α) is a transcription factor that is frequently stabilized and active in human clear cell renal cell carcinoma (ccRCC). We have found that constitutively active HIF1α is sufficient to cause neoplastic transformation in a murine model of ccRCC termed the TRACK model. RNA sequencing (RNAseq) and untargeted metabolomics analyses of samples from TRACK kidneys demonstrate that HIF1α activates the transcription of genes that cause increased glucose uptake, glycolysis, and lactate production, as well as a decrease in the flux of pyruvate entering the tricarboxylic acid (TCA) cycle and a decrease in oxidative phosphorylation; these changes are identical to those observed in human ccRCC samples. These studies show that a constitutively active HIF1α promotes tumorigenesis in TRACK mice by mediating a metabolic switch to aerobic glycolysis, i.e., the Warburg effect, and suggest that TRACK mice are a valid model to test novel therapies targeting metabolic changes to inhibit human ccRCC.

缺氧诱导因子1α（Hypoxia inducible factor 1 alpha, HIF1α）是一类转录因子，在人类透明细胞肾细胞癌（Clear cell renal cell carcinoma, ccRCC）中常发生稳定活化。我们的研究发现，在名为TRACK模型的ccRCC小鼠模型中，组成型激活的HIF1α足以诱发肿瘤转化。对TRACK模型小鼠肾脏样本进行RNA测序（RNA sequencing, RNAseq）与非靶向代谢组学分析后显示，HIF1α可激活相关基因的转录，促使葡萄糖摄取、糖酵解及乳酸生成增加，同时降低丙酮酸进入三羧酸循环（Tricarboxylic acid cycle, TCA循环）的通量，并抑制氧化磷酸化过程；上述变化与人类ccRCC样本中的观测结果完全一致。本研究证实，组成型激活的HIF1α通过介导代谢重编程转向有氧糖酵解（即瓦伯格效应，Warburg effect），促进TRACK小鼠的肿瘤发生，并提示TRACK小鼠是检验靶向代谢改变以抑制人类ccRCC的新型疗法的可靠模型。