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...

Purpose: Inactivation of vonHippel-Lindau (VHL) gene in clear-cell renal cell carcinoma (RCC) leads to increased levels of hypoxia-inducible factors (HIF) andoverexpression ofHIF target genes, such as VEGF and others. VEGF-targeted agents are standard in advanced clear-cell RCC but biomarkers of activity are lacking. Experimental Design: We analyzed tumor tissue samples from metastatic clear-ce...

H ypoxia has been identified as a common environmental stress factor associated with therapeutic resistance and metastasis in human cancers. A major player in regulating the response to hypoxia is the transcriptional factor hypoxia-inducible factor 1 alpha (HIF-1a). Although HIF-1a is well known to be stabilized under hypoxia, the regulatory mechanism of HIF-1a signaling in malignant cells is n...

Background : The epithelial mesenchymal transition (EMT) is intimately associated with tumor hypoxia. The present study was conducted to investigate the immunohistochemical relationship between hypoxic and EMT-related molecules in non-small cell lung carcinoma (NSCLC). Methods : Immunohistochemical staining for hypoxia inducible factor (HIF)-1a, carbonic anhydrase (CA) IX, TWIST, and E-cadherin...

HIF-1a, one of the most extensively studied oncogenes, is activated by a variety of microenvironmental factors. The resulting biological effects are thought to depend on its transcriptional activity. The RNAse enzyme Dicer is frequently downregulated in human cancers, which has been functionally linked to enhanced metastatic properties; however, current knowledge of the upstream mechanisms regu...

The pathobiology of chronic obstructive pulmonary disease (COPD) is not completely understood. The aim of this study was to assess the expression of hypoxia inducible factor (HIF)-1a in lung tissue from patients with COPD/emphysema. Lung tissue samples from 26 patients were included in this study. Seven samples were obtained from patients with normal lung function, the remainder of the samples ...

Hypoxia-inducible factor-1 (HIF-1) is a transcriptional complex that is activated in response to hypoxia and growth factors. HIF-1 plays a central role in tumor progression, invasion, and metastasis. Overexpression of the HIF-1A subunit has been observed in many human cancers and is associated with a poor prognostic outcome with conventional treatments. Targeting HIF-1 using novel small molecul...

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Recently, we have shown that insulin-like growth factor-I and serum-derived growth factors stimulate VEGF expression in neuroblastoma cells via induction of hypoxiainducible factor-1A (HIF-1A). Because another ...

In human neuroblastoma, amplification of theMYCN gene predicts poor prognosis and resistance to therapy. Because hypoxia contributes to aggressive tumor phenotypes, predominantly via two structurally related hypoxia inducible factors, HIF-1a and HIF-2a, we examined hypoxia responses inMYCN-amplified neuroblastoma cells. We demonstrate here that HIF-1a, but not HIF-2a, is preferentially expresse...

The switch to an angiogenic phenotype is a fundamental determinant of neoplastic growth and tumor progression. We demonstrate that homozygous deletion of the p53 tumor suppressor gene via homologous recombination in a human cancer cell line promotes the neovascularization and growth of tumor xenografts in nude mice. We find that p53 promotes Mdm2-mediated ubiquitination and proteasomal degradat...