29 research outputs found
Altered VEGF splicing isoform balance in tumor endothelium involves activation of splicing factors Srpk1 and Srsf1 by the Wilmsâ tumor suppressor Wt1
Angiogenesis is one hallmark of cancer. Vascular endothelial growth factor (VEGF) is a known inducer of angiogenesis. Many patients benefit from antiangiogenic therapies, which however have limitations. Although VEGF is overexpressed in most tumors, different VEGF isoforms with distinct angiogenic properties are produced through alternative splicing. In podocytes, the Wilmsâ tumor suppressor 1 (WT1) suppresses the Serine/arginine-rich protein-specific splicing factor kinase (SRPK1), and indirectly Serine/arginine-rich splicing factor 1 (Srsf1) activity, and alters VEGF splicing. We analyzed VEGF isoforms, Wt1, Srpk1, and Srsf1 in normal and tumor endothelium. Wt1, Srpk1, Srsf1, and the angiogenic VEGF164a isoform were highly expressed in tumor endothelium compared to normal lung endothelium. Nuclear expression of Srsf1 was detectable in the endothelium of various tumor types, but not in healthy tissues. Inducible conditional vessel-specific knockout of Wt1 reduced Wt1, Srpk1, and Srsf1 expression in endothelial cells and induced a shift towards the antiangiogenic VEGF120 isoform. Wt1(âKTS) directly binds and activates both the promoters of Srpk1 and Srsf1 in endothelial cells. In conclusion, Wt1 activates Srpk1 and Srsf1 and induces expression of angiogenic VEGF isoforms in tumor endothelium
PPARÎČ activation inhibits melanoma cell proliferation involving repression of the Wilmsâ tumour suppressor WT1
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that strongly influence molecular signalling in normal and cancer cells. Although increasing evidence suggests a role of PPARs in skin carcinogenesis, only expression of PPARÎł has been investigated in human melanoma tissues. Activation of PPARα has been shown to inhibit the metastatic potential, whereas stimulation of PPARÎł decreased melanoma cell proliferation. We show here that the third member of the PPAR family, PPARÎČ/ÎŽ is expressed in human melanoma samples. Specific pharmacological activation of PPARÎČ using GW0742 or GW501516 in low concentrations inhibits proliferation of human and murine melanoma cells. Inhibition of proliferation is accompanied by decreased expression of the Wilmsâ tumour suppressor 1 (WT1), which is implicated in melanoma proliferation. We demonstrate that PPARÎČ directly represses WT1 as (1) PPARÎČ activation represses WT1 promoter activity; (2) in chromatin immunoprecipitation and electrophoretic mobility shift assays, we identified a binding element for PPARÎČ in the WT1 promoter; (3) deletion of this binding element abolishes repression by PPARÎČ and (4) the WT1 downstream molecules nestin and zyxin are down-regulated upon PPARÎČ activation. Our findings elucidate a novel mechanism of signalling by ligands of PPARÎČ, which leads to suppression of melanoma cell growth through direct repression of WT1
[Human dirofilariasis: 3 cases in the south of France]
INTRODUCTION: Dirofilariasis is a zoonosis usually found in dogs and cats. It is rare in humans, who are dead-end hosts for the parasite. CASES: We report 3 cases of subcutaneous dirofilariasis due to Dirofilaria repens, contracted in the south of France (Alpes-Maritimes and Corsica). In the first two cases, the dirofilariasis manifested as lymph node enlargement; in the third case, lung disease suggested a systemic diffusion of microfilariae. DISCUSSION: Dirofilaria repens dirofilariasis is due to the transmission of microfilariae by some mosquito bites (Aedes, Culex, Anopheles, Mansonia, Psorophora and Taeniorhynchus). Usually only one larva develops, producing an immature adult worm inside a node. Ultrasound examination may suggest the parasitic origin of the lesion. It is treated surgically, by excision, without chemotherapy. Very rarely, an adult worm may mature and produce systemic diffusion of microfilariae. The nodule in the third case contained a gravid adult female worm but we found no microfilariae. Dirofilariosis can present problems in diagnosis and treatment. It must be considered in patients with an isolated nodule
Vascular PPARÎČ/ÎŽ Promotes Tumor Angiogenesis and Progression
International audiencePeroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which function as transcription factors. Among them, PPARÎČ/ÎŽ is highly expressed in endothelial cells. Pharmacological activation with PPARÎČ/ÎŽ agonists had been shown to increase their angiogenic properties. PPARÎČ/ÎŽ has been suggested to be involved in the regulation of the angiogenic switch in tumor progression. However, until now, it is not clear to what extent the expression of PPARÎČ/ÎŽ in tumor endothelium influences tumor progression and metastasis formation. We addressed this question using transgenic mice with an inducible conditional vascular-specific overexpression of PPARÎČ/ÎŽ. Following specific over-expression of PPARÎČ/ÎŽ in endothelial cells, we induced syngenic tumors. We observed an enhanced tumor growth, a higher vessel density, and enhanced metastasis formation in the tumors of animals with vessel-specific overexpression of PPARÎČ/ÎŽ. In order to identify molecular downstream targets of PPARÎČ/ÎŽ in the tumor endothelium, we sorted endothelial cells from the tumors and performed RNA sequencing. We identified platelet-derived growth factor receptor beta (Pdgfrb), platelet-derived growth factor subunit B (Pdgfb), and the tyrosinkinase KIT (c-Kit) as new PPARÎČ/ÎŽ -dependent molecules. We show here that PPARÎČ/ÎŽ activation, regardless of its action on different cancer cell types, leads to a higher tumor vascularization which favors tumor growth and metastasis formation
Lethal Form of KeratitisâIchthyosisâDeafness Syndrome Caused by the GJB2 Mutation p.Ser17Phe
International audienceKeratosisâIchthyosisâDeafness (KID) syndrome is a rare form of ichthyosis caused by mutations in the gene GJB2 encoding the gap junction protein connexin 26 (Cx26). Connexins are a family of integral membrane proteins forming gap junction channels that control and coordinate a variety of cellular activities through the exchange of small ions, metabolites and signalling molecules
Efficacy and safety of 0.05% ingenol mebutate in the treatment of basal cell carcinoma: A prospective study
Apoptosis and pericyte loss in alveolar capillaries in COVID-19 infection: choice of markers matters. Authorâs reply
Fatal cerebral malaria diagnosed after death in a French patient.
International audienceWe report on the case of a French citizen who was found dead in his home, 4 days after returning from Cameroon. The patient died of imported malaria, as revealed by the postmortem investigations. Few such cases have been reported throughout the world. This article reviews deaths due to malaria diagnosed at the time of autopsy in France between 1995 and 2005. We conclude that the nonspecific symptoms of malaria can lead to a misdiagnosis and the need for a forensic expert to intervene at the scene of death, which usually occurs in the home. We will remind forensic pathologists of the clinical, biologic, and forensic aspects of this infectious disease. In particular, the uses of microbiologic analyses, the QBC malaria test and the Core malaria Pan/Pv/pf test as well as brain tissue histology will be reviewed