a Ligand and Its Receptor von Hippel-Lindau Loss-of-Function Induces Expression of Hemangioblastoma and Clear Cell-Renal Cell Carcinoma: and CXCR4 Expression

The genetic hallmark of hemangioblastomas and clear cellrenal cell carcinomas (CC-RCCs) is loss-of-function of the von Hippel-Lindau (VHL) tumor suppressor protein. VHL is required for oxygen-dependent degradation of hypoxiainducible factor-1A (HIF-1A). In hemangioblastomas and CC-RCCs, HIF-1A is constitutively overexpressed leading to increased transcription of HIF-1–regulated genes, including vascular endothelial growth factor (VEGF). Because loss of VHL function is associated with increased expression of the chemokine receptor CXCR4 in CC-RCCs, we investigated the expression of HIF-1A, CXCR4, and its ligand stromal cell– derived factor-1A (SDF-1A) in hemangioblastomas and CCRCCs. Immunohistochemistry revealed overexpression of both CXCR4 and SDF-1A within tumor cells and endothelial cells of hemangioblastomas and CC-RCCs. HIF-1A was detected in tumor cell nuclei of both hemangioblastomas and CC-RCCs. A specific ELISA showed that hemangioblastomas and CC-RCCs expressed SDF-1A protein at levels that were significantly higher than those found in normal tissue. Analysis of the VHL-null RCC line 786-0 revealed that SDF-1A mRNA levels were 100-fold higher than in a subclone transfected with the wild-type VHL gene. Expression of CXCR4 and SDF-1A mRNA was significantly decreased in HIF-1A-null compared with wild-type mouse embryo fibroblasts (MEFs). ELISA and Western blot studies for SDF-1A and CXCR4 protein expression confirmed the RNA findings in RCC lines and MEFs. These results suggest that loss-of-function of a single tumor suppressor gene can up-regulate the expression of both a ligand and its receptor, which may establish an autocrine signaling pathway with important roles in the pathogenesis of hemangioblastoma and CC-RCC. (Cancer Res 2005; 65(14): 6178-88)