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Papillomaviruses (PVs) are widespread pathogens. However, the extent of PV infections in bats remains largely unknown. This work represents the first comprehensive study of PVs in Iberian bats. We identified four novel PVs in the mucosa of free-ranging Eptesicus serotinus (EserPV1, EserPV2, and EserPV3) and Rhinolophus ferrumequinum (RferPV1) individuals and analyzed their phylogenetic relationships within the viral family. We further assessed their prevalence in different populations of E. serotinus and its close relative E. isabellinus. Although it is frequent to read that PVs co-evolve with their host, that PVs are highly species-specific, and that PVs do not usually recombine, our results suggest otherwise. First, strict virus-host co-evolution is rejected by the existence of five, distantly related bat PV lineages and by the lack of congruence between bats and bat PVs phylogenies. Second, the ability of EserPV2 and EserPV3 to infect two different bat species (E. serotinus and E. isabellinus) argues against strict host specificity. Finally, the description of a second noncoding region in the RferPV1 genome reinforces the view of an increased susceptibility to recombination in the E2-L2 genomic region. These findings prompt the question of whether the prevailing paradigms regarding PVs evolution should be reconsidered. Source

Romero O.A.,Bellvitge Biomedical Research Institute IDIBELL | Setien F.,Bellvitge Biomedical Research Institute IDIBELL | John S.,U.S. National Institutes of Health | Gimenez-Xavier P.,Bellvitge Biomedical Research Institute IDIBELL | And 6 more authors.
EMBO Molecular Medicine

BRG1, a member of the SWI/SNF complex, is mutated in cancer, but it is unclear how it promotes tumourigenesis. We report that re-expression of BRG1 in lung cancer cells up-regulates lung-specific transcripts, restoring the gene expression signature of normal lung. Using cell lines from several cancer types we found that those lacking BRG1 do not respond to retinoic acid (RA) or glucocorticoids (GC), while restoration of BRG1 restores sensitivity. Conversely, in SH-SY5Y cells, a paradigm of RA-dependent differentiation, abrogation of BRG1 prevented the response to RA. Further, our data suggest an antagonistic functional connection between BRG1 and MYC, whereby, refractoriness to RA and GC by BRG1 inactivation involves deregulation of MYC activity. Mechanistically, some of these effects are mediated by BRG1 binding to MYC and MYC-target promoters. The BRG1-MYC antagonism was also evident in primary tumours. Finally, BRG1 restoration significantly dampened invasion and progression and decreased MYC in lung cancer cells orthotopically implanted in nude mice. Thus, BRG1 inactivation enables cancer cells to sustain undifferentiated gene expression programs and prevent its response to environmental stimuli. © 2012 EMBO Molecular Medicine. Source

Bedhomme S.,Institute Biologia Molecular Y Celular Of Plantas | Bedhomme S.,Catalan Institute of Oncology ICO | Lafforgue G.,Institute Biologia Molecular Y Celular Of Plantas | Elena S.F.,Institute Biologia Molecular Y Celular Of Plantas | Elena S.F.,Santa Fe Institute
BMC Evolutionary Biology

Background: The importance of historical contingency in determining the potential of viral populations to evolve has been largely unappreciated. Identifying the constraints imposed by past adaptations is, however, of importance for understanding many questions in evolutionary biology, such as the evolution of host usage dynamics by multi-host viruses or the emergence of escape mutants that persist in the absence of antiviral treatments. To address this issue, we undertook an experimental approach in which sixty lineages of Tobacco etch potyvirus that differ in their past evolutionary history and degree of adaptation to Nicotiana tabacum were allowed to adapt to this host for 15 rounds of within host multiplication and transfer. We thereafter evaluated the degree of adaptation to the new host as well as to the original ones and characterized the consensus sequence of each lineage. Results: We found that past evolutionary history did not determine the phenotypic outcome of this common host evolution phase, and that the signal of local adaptation to past hosts had largely disappeared. By contrast, evolutionary history left footprints at the genotypic level, since the majority of host-specific mutations present at the beginning of this experiment were retained in the end-point populations and may have affected which new mutations were consequently fixed. This resulted in further divergence between the sequences despite a shared selective environment. Conclusions: The present experiment reinforces the idea that the answer to the question "How important is historical contingency in evolution?" strongly depends on the level of integration of the traits studied. A strong historical contingency was found for TEV genotype, whereas a weak effect of on phenotypic evolution was revealed. In an applied context, our results imply that viruses are not easily trapped into suboptimal phenotypes and that (re)emergence is not evolutionarily constrained. © 2013 Bedhomme et al; licensee BioMed Central Ltd. Source

Duell E.J.,Catalan Institute of Oncology ICO
Molecular Carcinogenesis

Tobacco smoking represents an important known cause of ductal pancreatic adenocarcinoma. Recent data from pooled analyses in consortia involving multiple case-control and cohort studies suggest that heavy (but not moderate or light) alcohol consumption also may increase pancreatic cancer risk. Animal and human evidence indicate that tobacco carcinogens and metabolites may act in concert and have both genetic and epigenetic effects at early and later stages in pancreatic tumorigenesis. One of the more important tobacco-related carcinogens, NNK, probably acts via multiple pathways. Heavy alcohol consumption may increase pancreatic cancer risk by potentiating the effects of other risk factors such as tobacco smoking, poor nutrition, and inflammatory pathways related to chronic pancreatitis, but also may have independent genetic and epigenetic effects. Animal and human studies of tobacco- and alcohol-related pancreatic carcinogenesis suggest multi-modal, overlapping mechanistic pathways. Tobacco smoking and heavy alcohol consumption are preventable exposures, and their avoidance would substantially decrease the burden of pancreatic cancer worldwide. © 2011 Wiley Periodicals, Inc.. Source

Iliou M.S.,Bellvitge Biomedical Research Institute IDIBELL | Da Silva-Diz V.,Bellvitge Biomedical Research Institute IDIBELL | Carmona F.J.,Bellvitge Biomedical Research Institute IDIBELL | Ramalho-Carvalho J.,Bellvitge Biomedical Research Institute IDIBELL | And 6 more authors.

Disruption of microRNA (miRNA) expression patterns is now being recognized as a hallmark of human cancer. The causes of these altered profiles are diverse, and, among them, we found the existence of defects in the miRNA processing machinery. However, little is known about how these alterations affect the biology of the underlying tumors. Herein, we show that colorectal cancer cells with an impairment in DICER1, a major miRNA biogenesis gene, undergo enrichment of tumor stemness features and an epithelial-to-mesenchymal transition. These phenotypes are associated with the downregulation of miRNAs, such as miR-34a, miR-126 and those of the miR-200 family, that target critical coding genes in these pathways. Most importantly, DICER1 impairment also induces the acquisition of a greater capacity for tumor initiation and metastasis, two properties associated with cancer stem cells. © 2014 Macmillan Publishers Limited. Source

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