Sequential functions of CPEB1 and CPEB4 regulate pathologic expression of vascular endothelial growth factor and angiogenesis in chronic liver disease.

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• dc.contributor.author Calderone, Vittorioca
• dc.contributor.author Gallego, Javierca
• dc.contributor.author Fernandez Miranda, Gonzaloca
• dc.contributor.author Garcia Pras, Esterca
• dc.contributor.author Maillo, Carlosca
• dc.contributor.author Berzigotti, Annalisaca
• dc.contributor.author Mejias, Marcca
• dc.contributor.author Bava, Felice Alessioca
• dc.contributor.author Angulo Urarte, Anaca
• dc.contributor.author Graupera, Marionaca
• dc.contributor.author Pilar, Navarro Medranoca
• dc.contributor.author Bosch, Jaimeca
• dc.contributor.author Fernandez, Mercedesca
• dc.contributor.author Méndez Giraldez, Raúlca
• dc.date.accessioned 2016-05-20T09:59:44Z
• dc.date.issued 2016
• dc.description.abstract BACKGROUND & AIMS: Vascular endothelial growth factor (VEGF) regulates angiogenesis, yet therapeutic strategies to disrupt VEGF signaling can interfere with physiologic angiogenesis. In a search for ways to inhibit pathologic production or activities of VEGF without affecting its normal production or functions, we investigated the post-transcriptional regulation of VEGF by the cytoplasmic polyadenylation element-binding proteins CPEB1 and CPEB4 during development of portal hypertension and liver disease. METHODS: We obtained transjugular liver biopsies from patients with hepatitis C virus-associated cirrhosis or liver tissues removed during transplantation; healthy human liver tissue was obtained from a commercial source (control). We also performed experiments with male Sprague-Dawley rats and CPEB-deficient mice (C57BL6 or mixed C57BL6/129 background) and their wild-type littermates. Secondary biliary cirrhosis was induced in rats by bile duct ligation, and portal hypertension was induced by partial portal vein ligation. Liver and mesenteric tissues were collected and analyzed in angiogenesis, reverse transcription polymerase chain reaction, polyA tail, 3' rapid amplification of complementary DNA ends, Southern blot, immunoblot, histologic, immunohistochemical, immunofluorescence, and confocal microscopy assays. CPEB was knocked down with small interfering RNAs in H5V endothelial cells, and translation of luciferase reporters constructs was assessed. RESULTS: Activation of CPEB1 promoted alternative nuclear processing within noncoding 3'-untranslated regions of VEGF and CPEB4 messenger RNAs in H5V cells, resulting in deletion of translation repressor elements. The subsequent overexpression of CPEB4 promoted cytoplasmic polyadenylation of VEGF messenger RNA, increasing its translation; the high levels of VEGF produced by these cells led to their formation of tubular structures in Matrigel assays. We observed increased levels of CPEB1 and CPEB4 in cirrhotic liver tissues from patients, compared with control tissue, as well as in livers and mesenteries of rats and mice with cirrhosis or/and portal hypertension. Mice with knockdown of CPEB1 or CPEB4 did not overexpress VEGF or have signs of mesenteric neovascularization, and developed less-severe forms of portal hypertension after portal vein ligation. CONCLUSIONS: We identified a mechanism of VEGF overexpression in liver and mesentery that promotes pathologic, but not physiologic, angiogenesis, via sequential and nonredundant functions of CPEB1 and CPEB4. Regulation of CPEB4 by CPEB1 and the CPEB4 autoamplification loop induces pathologic angiogenesis. Strategies to block the activities of CPEBs might be developed to treat chronic liver and other angiogenesis-dependent diseases.ca
• dc.description.sponsorship This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2011-29491 and SAF2014-55473-R to MF; BFU2011-30121, BFU2014-54122-P and Consolider RNAREG CSD2009-00080 to RM; PI13/00341 to JB; PI11/01562 and PI14/00125 to PN), Generalitat de Catalunya (SGR1436 to RM; SGR1108 to JB), Fundación Botín by Banco Santander through its Santander Universities Global Division (to RM), AECC Scientific Foundation (to RM and MF), Worldwide Cancer Research (to RM and MF) and RETIC Cancer RD12/0036/0051/FEDER to PN. GFM is funded by a Juan de la Cierva contract from MINECO. IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). CIBERehd is an initiative from the Instituto de Salud Carlos III. We also thank Dr Francisco X Real for his contribution to knockout mice generation.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Calderone V, Gallego J, Fernandez-Miranda G, Garcia-Pras E, Maillo C, Berzigotti A. et al. Sequential functions of CPEB1 and CPEB4 regulate pathologic expression of vascular endothelial growth factor and angiogenesis in chronic liver disease. Gastroenterology. 2016 Apr;150(4):982-997.e30. doi: 10.1053/j.gastro.2015.11.038ca
• dc.identifier.doi http://dx.doi.org/10.1053/j.gastro.2015.11.038
• dc.identifier.issn 0016-5085
• dc.identifier.uri http://hdl.handle.net/10230/26310
• dc.language.iso engca
• dc.publisher Elsevierca
• dc.relation.ispartof Gastroenterology. 2016 Apr;150(4):982-97
• dc.rights © Elsevier http://dx.doi.org/10.1053/j.gastro.2015.11.038ca
• dc.rights.accessRights info:eu-repo/semantics/openAccessca
• dc.subject.other Angiogènesica
• dc.subject.other Hipertensió portalca
• dc.subject.other Fetge -- Malaltiesca
• dc.title Sequential functions of CPEB1 and CPEB4 regulate pathologic expression of vascular endothelial growth factor and angiogenesis in chronic liver disease.ca
• dc.type info:eu-repo/semantics/articleca
• dc.type.version info:eu-repo/semantics/acceptedVersionca