Figure 2.

Contrasting Role of HIF-1α and HIF-2α in ccRCC progression. Loss of VHL leads to the upregulation of HIF-α isoforms: HIF-1α and HIF-2α, irrespective of oxygen availability in cell, which in turn contributes to the formation of initial renal cysts and tumors. Interestingly, only the HIF-1α isoform is expressed in normal tubular cells and the initiation of HIF-2α expression upon VHL loss, acts as an initial trigger for transformation of healthy tubular cells. Overtime, the expression of HIF-2α prevails over HIF-1α expression, which is associated with tumor growth, progression and metastasis. Furthermore, HIF-1α attenuates expression of several pro-tumorigenic genes which otherwise are stimulated by HIF-2α suppressing the malignant phenotype.