Stromal cell-derived factor-1α and CXCR4 expression in hemangioblastoma and clear cell-renal cell carcinoma: Von Hippel-Lindau loss-of-function induces expression of a ligand and its receptor

David Zagzag, Balaji Krishnamachary, Herman Yee, Hiroaki Okuyama, Luis Chiriboga, M. Aktar Ali, Jonathan Melamed, Gregg L. Semenza

Research output: Contribution to journalArticlepeer-review

215 Scopus citations

Abstract

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-1α (HIF-1α). In hemangioblastomas and CC-RCCs, HIF-1α 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-1α, CXCR4, and its ligand stromal cell-derived factor-1α (SDF-1α) in hemangioblastomas and CC-RCCs. Immunohistochemistry revealed overexpression of both CXCR4 and SDF-1α within tumor cells and endothelial cells of hemangioblastomas and CC-RCCs. HIF-1α was detected in tumor cell nuclei of both hemangioblastomas and CC-RCCs. A specific ELISA showed that hemangioblastomas and CC-RCCs expressed SDF-1α 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-1α mRNA levels were 100-fold higher than in a subclone transfected with the wild-type VHL gene. Expression of CXCR4 and SDF-1α mRNA was significantly decreased in HIF-1α-null compared with wild-type mouse embryo fibroblasts (MEFs). ELISA and Western blot studies for SDF-1α 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.

Original languageEnglish (US)
Pages (from-to)6178-6188
Number of pages11
JournalCancer research
Volume65
Issue number14
DOIs
StatePublished - Jul 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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