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Romanelli V.,Institute Dinvestigacio Biomedica Of Bellvitge | Nakabayashi K.,National Health Research Institute | Vizoso M.,Institute Dinvestigacio Biomedica Of Bellvitge | Moran S.,Institute Dinvestigacio Biomedica Of Bellvitge | And 9 more authors.
Epigenetics | Year: 2014

Cancer is as much an epigenetic disease as a genetic one; however, the interplay between these two processes is unclear. Recently, it has been shown that a large proportion of DNA methylation variability can be explained by allelespecific methylation (AS M), either at classical imprinted loci or those regulated by underlying genetic variants. During a recent screen for imprinted differentially methylated regions, we identified the genomic interval overlapping the noncoding nc886 RNA (previously known as vtRNA2-1) as an atypical AS M that shows variable levels of methylation, predominantly on the maternal allele in many tissues. Here we show that the nc886 interval is the first example of a polymorphic imprinted DMR in humans. Further analysis of the region suggests that the interval subjected to AS M is approximately 2 kb in size and somatically acquired. An in depth analysis of this region in primary cancer samples with matching normal adjacent tissue from the Cancer Genome Atlas revealed that aberrant methylation in bladder, breast, colon and lung tumors occurred in approximately 27% of cases. Hypermethylation occurred more frequently than hypomethylation. Using additional normal-tumor paired samples we show that on rare occasions the aberrant methylation profile is due to loss-of-heterozygosity. This work therefore suggests that the nc886 locus is subject to variable allelic methylation that undergoes cancer-associated epigenetic changes in solid tumors. © 2014 Landes Bioscience.

Garcia N.A.,Institute Investigacion Sanitaria La Fe | Ontoria-Oviedo I.,Institute Investigacion Sanitaria La Fe | Gonzalez-King H.,Institute Investigacion Sanitaria La Fe | Diez-Juan A.,Fundacion IVI | Sepulveda P.,Institute Investigacion Sanitaria La Fe
PLoS ONE | Year: 2015

Cardiomyocytes (CMs) and endothelial cells (ECs) have an intimate anatomical relationship that is essential for maintaining normal development and function in the heart. Little is known about the mechanisms that regulate cardiac and endothelial crosstalk, particularly in situations of acute stress when local active processes are required to regulate endothelial function. We examined whether CM-derived exosomes could modulate endothelial function. Under conditions of glucose deprivation, immortalized H9C2 cardiomyocytes increase their secretion of exosomes. CM-derived exosomes are loaded with a broad repertoire of miRNA and proteins in a glucose availability-dependent manner. Gene Ontology (GO) analysis of exosome cargo molecules identified an enrichment of biological process that could alter EC activity. We observed that addition of CM-derived exosomes to ECs induced changes in transcriptional activity of pro-angiogenic genes. Finally, we demonstrated that incubation of H9C2-derived exosomes with ECs induced proliferation and angiogenesis in the latter. Thus, exosome-mediated communication between CM and EC establishes a functional relationship that could have potential implications for the induction of local neovascularization during acute situations such as cardiac injury. © 2015 Garcia et al.

Evans G.E.,University of Otago | Martinez-Conejero J.A.,Fundacion IVI | Phillipson G.T.M.,Fertility Assoc. | Sykes P.H.,University of Otago | And 7 more authors.
Fertility and Sterility | Year: 2014

Objective To characterize the transcriptome of luminal epithelia (LE) of fertile secretory endometria and compare the results with those from glandular epithelia (GE). Design Endometrial samples were collected at 2 and 7 days after initial blood LH surge in separate menstrual cycles. LE were obtained with the use of laser microdissection. mRNA was amplified with the use of linear polymerase chain reaction and hybridized to Agilent 4×44 microarrays. Gene analysis was used to identify differentially expressed mRNAs. Immunohistochemistry was used to assess nine proteins. Setting One IVF clinic. Patient(s) Seven Caucasian fertile cycling women. Intervention(s) None. Main Outcome Measure(s) Cycle dating with the use of blood endocrinologic markers, microarrays of laser-microdissected LE, immunohistochemical analysis. Result(s) One hundred sixty-one (of 401) differentially expressed mRNAs in LE were identified from the metabolism pathway. Increased selective protein expression in LE at 7 days after initial LH surge was observed. LE mRNA expression was the converse of that in GE. The two cell types each had a different significant biologic pathway identified. Conclusion(s) Our results introduce a new concept that LE differentially expressed mRNAs are in the converse direction to that of GE, indicating different biologic processes despite the GE being continuous with the luminal monolayer. This probable distinction of biologic roles has not been noted previously. Further investigations must take cognizance of this observation. © 2014 by American Society for Reproductive Medicine.

Ferrero H.,Fundacion IVI | Ferrero H.,Instituto Universitario | Garcia-Pascual C.M.,Fundacion IVI | Garcia-Pascual C.M.,Instituto Universitario | And 6 more authors.
Reproductive Biology and Endocrinology | Year: 2015

Background: Dopamine receptor 2 agonists (D2-ags) inhibit vascular endothelial growth factor (VEGF) secretion in luteinized granulosa cells (LGCs) both in vitro and in vivo. However, the mechanism of D2 regulation of the VEGF/VEGF Receptor 2 (VEGFR-2) pathway remains to be elucidated. We sought to determine the effects of D2 signaling on VEGF transcription and translation in LGCs, with the expectation of identifying potential D2-ag-based therapies for ovarian hyperstimulation syndrome (OHSS). Findings: LGCs from egg donors were cultured with chorionic gonadotropin (hCG) in the presence of Actinomycin-D (ActD) or Brefeldin-A (BFA) to evaluate the effects of a D2-ag, cabergoline (Cb2), on VEGF secretion. The contribution of the conventional Gi/Go, Gz and AKT/β-Arrestin pathways in the VEGF regulation was assessed by adding pertussis toxin (PTX), phorbol 12-myristate 13-acetate (PMA), or wortmannin (WT). While Cb2 inhibited VEGF secretion by interfering with VEGF peptide translation and secretion, inhibition of conventional D2 transduction pathways did not reverse Cb2-mediated inhibition of VEGF secretion. Conclusions: The effects of D2-ag on VEGF translation and secretion are mediated by D2 signaling pathways that have yet to be described. We found that D2-ag inhibits VEGF secretion at the post-transcriptional level, suggesting that D2-ag treatment should be combined with therapies that inhibit VEGF transcription, such as the employment of LH or GnRH for triggering ovulation, to improve the efficacy of OHSS prevention. © 2015 Ferrero et al.

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