CXCR4 and neoplasm: These studies further suggest that the loss or functional inactivation of the protein product of VHL, a tumor suppressor gene commonly mutated in clear cell RCC, results in persistent activation of HIF-1α and a dramatic increase in CXCR4 expression due to loss of its ability to target HIF-1α for degradation by the 26S proteasome [33,34,44].