ABSTRACT
Renal cell carcinoma (RCC) is the major cause of death among patients with von Hippel-Lindau (VHL) disease. Resistance to therapies targeting tumor angiogenesis opens the question about the underlying mechanisms. Previously we have described that RWDD3 or RSUME (RWD domain-containing protein SUMO Enhancer) sumoylates and binds VHL protein and negatively regulates HIF degradation, leading to xenograft RCC tumor growth in mice. In this study, we performed a bioinformatics analysis in a ccRCC dataset showing an association of RSUME levels with VHL mutations and tumor progression, and we demonstrate the molecular mechanism by which RSUME regulates the pathologic angiogenic phenotype of VHL missense mutations. We report that VHL mutants fail to downregulate RSUME protein levels accounting for the increased RSUME expression found in RCC tumors. Furthermore, we prove that targeting RSUME in RCC cell line clones carrying missense VHL mutants results in decreased early tumor angiogenesis. The mechanism we describe is that RSUME sumoylates VHL mutants and beyond its sumoylation capacity, interacts with Type 2 VHL mutants, reduces HIF-2α-VHL mutants binding, and negatively regulates the assembly of the Type 2 VHL, Elongins and Cullins (ECV) complex. Altogether these results show RSUME involvement in VHL mutants deregulation that leads to the angiogenic phenotype of RCC tumors.
Subject(s)
Carcinoma, Renal Cell/genetics , Kidney Neoplasms/genetics , Transcription Factors/metabolism , Von Hippel-Lindau Tumor Suppressor Protein/genetics , von Hippel-Lindau Disease/genetics , Animals , COS Cells , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/mortality , Cell Line, Tumor , Chlorocebus aethiops , Culture Media, Conditioned , Elongin/genetics , Elongin/metabolism , Gene Expression Regulation, Neoplastic , Human Umbilical Vein Endothelial Cells , Humans , Kidney Neoplasms/metabolism , Kidney Neoplasms/mortality , Male , Mice , Mice, Inbred NOD , Mice, SCID , Mutation, Missense , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/metabolism , Sumoylation , Transcription Factors/genetics , Von Hippel-Lindau Tumor Suppressor Protein/metabolism , von Hippel-Lindau Disease/complications , von Hippel-Lindau Disease/metabolismABSTRACT
BACKGROUND: Minimally invasive techniques for surfactant administration for infants with respiratory distress syndrome (RDS) of moderate severity have been proposed. The laryngeal mask airway (LMA) helps in securing the airway without the need of laryngoscopy, but still requires the use of positive pressure ventilation (PPV) to flush surfactant into the lungs. OBJECTIVE: This article compares the effectiveness of two techniques for LMA surfactant administration, instillation into the LMA lumen followed by PPV versus direct laryngeal instillation through a preinserted feeding tube inside the LMA during spontaneous respirations. STUDY DESIGN: This is a randomized controlled trial (RCT) of 18 rabbits with acquired respiratory distress after lung lavage. After surfactant was given, the rabbits remained on continuous positive airway pressure (CPAP). Gas exchange parameters were assessed at baseline and at 30 minutes and lung parenchyma pathology features were analyzed. RESULTS: Time required for surfactant administration, oxygenation improvement, and histopathologic findings did not differ between groups. The new technique decreased the need of PPV (p < 0.05). CONCLUSION: In this animal model, surfactant administration through a preinserted feeding tube within the LMA lumen is safe and effective while providing the benefits of a minimally invasive approach. This technique reduces the need of PPV and may prevent its potential risks.
