HIF-2α downregulation in the absence of functional VHL is not sufficient for renal cell differentiation

<p>Abstract</p> <p>Background</p> <p>Mutational inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene has been linked to hereditary as well as sporadic clear cell renal carcinomas. The product of the VHL gene, pVHL, acts to target hypoxia-inducible factor alpha (HIF-α) subunits for ubiquitination and subsequent degradation. Using an RNA interference approach to lower levels of HIF-2α in two different renal cell lines that lack functional pVHL, we have tested the contribution of HIF-2α toward cellular pVHL activities.</p> <p>Results</p> <p>Knockdown of HIF-2α resulted in cell cycle arrest of renal cells that were grown on collagen I, indicating that this pVHL function is dependent on HIF-2α regulation. However, cellular morphological changes and downregulation of integrins α5 and β1, which were seen upon pVHL replacement, were not faithfully phenocopied by HIF-2α reduction. Moreover, fibronectin deposition and expression of renal cell differentiation markers were observed in cells containing replaced pVHL, but not in HIF-2α knockdown cells, indicating that these pVHL functions may occur independently of HIF-2α downregulation.</p> <p>Conclusion</p> <p>These results indicate that HIF-2α regulation is not sufficient for pVHL-induced renal cell differentiation. We hypothesize that in addition to HIF-2α dysregulation, abrogation of additional pVHL functions is required for the initiation of renal carcinogenesis.</p

Early signs of metabolic syndrome in pediatric central nervous system tumor survivors after high-dose chemotherapy and autologous stem-cell transplantation and radiation.

PURPOSE: Cancer survivors treated with stem-cell transplant (SCT) and radiation therapy are at a high risk for late effects including the metabolic syndrome. This study reviewed the prevalence of the metabolic syndrome in pediatric central nervous system (CNS) tumor survivors treated with autologous SCT and craniospinal radiation. METHODS: A prospective, cross-sectional study in pediatric CNS tumor patients, who underwent a one-time evaluation at least 18 months post-autologous SCT for the presence of components of metabolic syndrome: obesity, hypertension, hyperlipidemia, and abnormal glucose levels. RESULTS: Twelve patients were evaluated, and two (16%) met full criteria for the metabolic syndrome. Seven patients (58%) had at least one component of metabolic syndrome: elevated glucose levels in 8% (1/12), obesity 17% (2/12), hypertriglyceridemia 17% (2/12), and reduced HDL cholesterol in 25% (3/12). None had hypertension. Nine patients (75%) demonstrated abnormal fasting lipid profiles with elevated total cholesterol levels, although only 25% (3/12) fulfilled criteria for a diagnosis of dyslipidemia. CONCLUSION: Pediatric CNS tumor survivors treated with autologous SCT and craniospinal radiation are at risk for early signs of metabolic syndrome, most commonly hyperlipidemia. Further studies evaluating the progression of these early signs to full criteria for the metabolic syndrome diagnosis are required