Journal
CANCER RESEARCH
Volume 65, Issue 14, Pages 6178-6188Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-04-4406
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Funding
- NCI NIH HHS [P50-CA103175, R01-CA100426] Funding Source: Medline
- NHLBI NIH HHS [R01-HL55338] Funding Source: Medline
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The genetic hallmark of hemangioblastomas and clear cell-renal 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 hypoxia-inducible factor-1 alpha (HIF-1 alpha). In hemangioblastomas and CC-RCCs, HIF-1 alpha 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-1 alpha, CXCR4, and its ligand stromal cell-derived factor-1 alpha (SDF-1 alpha) in hemangioblastomas and CC-RCCs. Immunohistochemistry revealed overexpression of both CXCR4 and SDF-1 alpha within tumor cells and endothelial cells of hemangioblastomas and CG-RCCs. HIF-1 alpha was detected in tumor cell nuclei of both hemangioblastomas and CG-RCCs. A specific ELISA showed that hemangioblastomas and CC-RCCs expressed SDF-1 alpha 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-1 alpha mRNA levels were 100-fold higher than in a subclone transfected with the wild-type VHL gene. Expression of CXCR4 and SDF-1 alpha mRNA was significantly decreased in HIF-1 alpha-null compared with wild-type mouse embryo fibroblasts (MEFs). ELISA and Western blot studies for SDF-1 alpha 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.
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