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Perez-Janices N.,Cancer Epigenetics Group | Blanco-Luquin I.,Cancer Epigenetics Group | Tunon M.T.,Complejo Hospitalario de Navarra | Barba-Ramos E.,Complejo Hospitalario de Navarra | And 11 more authors.
Oncotarget | Year: 2015

Hypermethylation of tumor suppressor genes is one of the hallmarks in the progression of brain tumors. Our objectives were to analyze the presence of the hypermethylation of EPB41L3, RASSF2 and TSP-1 genes in 132 diffuse gliomas (astrocytic and oligodendroglial tumors) and in 10 cases of normal brain, and to establish their association with the patients' clinicopathological characteristics. Gene hypermethylation was analyzed by methylation-specific-PCR and confirmed by pyrosequencing (for EPB41L3 and TSP-1) and bisulfite-sequencing (for RASSF2).EPB41L3, RASSF2 and TSP-1 genes were hypermethylated only in tumors (29%, 10.6%, and 50%, respectively), confirming their cancer-specific role. Treatment of cells with the DNA-demethylating-agent 5-aza-2'-deoxycytidine restores their transcription, as confirmed by quantitative-reverse-transcription-PCR and immunofluorescence. Immunohistochemistry for EPB41L3, RASSF2 and TSP-1 was performed to analyze protein expression; p53, ki-67, and CD31 expression and 1p/19q co-deletion were considered to better characterize the tumors. EPB41L3 and TSP-1 hypermethylation was associated with worse (p = 0.047) and better (p = 0.037) prognosis, respectively. This observation was confirmed after adjusting the results for age and tumor grade, the role of TSP-1 being most pronounced in oligodendrogliomas (p = 0.001). We conclude that EPB41L3, RASSF2 and TSP-1 genes are involved in the pathogenesis of diffuse gliomas, and that EPB41L3 and TSP-1 hypermethylation are of prognostic significance. Source

Piazzolla D.,Tumour Suppression Group | Palla A.R.,Tumour Suppression Group | Pantoja C.,Tumour Suppression Group | Canamero M.,Histopathology Core Unit | And 16 more authors.
Nature Communications | Year: 2014

NANOG is a pluripotency transcription factor in embryonic stem cells; however, its role in adult tissues remains largely unexplored. Here we show that mouse NANOG is selectively expressed in stratified epithelia, most notably in the oesophagus where the Nanog promoter is hypomethylated. Interestingly, inducible ubiquitous overexpression of NANOG in mice causes hyperplasia selectively in the oesophagus, in association with increased cell proliferation. NANOG transcriptionally activates the mitotic programme, including Aurora A kinase (Aurka), in stratified epithelia, and endogenous NANOG directly binds to the Aurka promoter in primary keratinocytes. Interestingly, overexpression of Nanog or Aurka in mice increased proliferation and aneuploidy in the oesophageal basal epithelium. Finally, inactivation of NANOG in cell lines from oesophageal or head and neck squamous cell carcinomas (ESCCs or HNSCCs, respectively) results in lower levels of AURKA and decreased proliferation, and NANOG and AURKA expression are positively correlated in HNSCCs. Together, these results indicate that NANOG has a lineage-restricted mitogenic function in stratified epithelia. © 2014 Macmillan Publishers Limited. All rights reserved. Source

de Castro I.P.,Cell Division and Cancer Group | Aguirre-Portoles C.,Cell Division and Cancer Group | Martin B.,French National Center for Scientific Research | Fernandez-Miranda G.,Cell Division and Cancer Group | And 5 more authors.
Frontiers in Oncology | Year: 2011

Aurora-A is a serine/threonine kinase that plays critical roles in centrosome maturation, spindle dynamics, and chromosome orientation and it is frequently over-expressed in human cancers. In this work, we show that Aurora-A interacts with the SUMO-conjugating enzyme UBC9 and co-localizes with SUMO1 in mitotic cells. Aurora-A can be SUMOylated in vitro and in vivo. Mutation of the highly conserved SUMOylation residue lysine 249 significantly disrupts Aurora-A SUMOylation and mitotic defects characterized by defective and multipolar spindles ensue. The Aurora-AK249R mutant has normal kinase activity but displays altered dynamics at the mitotic spindle. In addition, ectopic expression of the Aurora-AK249R mutant results in a significant increase in susceptibility to malignant transformation induced by the Ras oncogene. These data suggest that modification by SUMO residues may control Aurora-A function at the spindle and that deficiency of SUMOylation of this kinase may have important implications for tumor development. © 2011 Pérez de Castro, Aguirre-Portolés, Martin, Fernández-Miranda, Klotzbucher, Kubbutat, Megías, Arlot-Bonnemains and Malumbres. Source

Epifano C.,Epithelial Cell Biology Group | Megias D.,Confocal Microscopy Core Unit | Perez-Moreno M.,Epithelial Cell Biology Group
EMBO Reports | Year: 2014

The adherens junction protein p120-catenin is implicated in the regulation of cadherin stability, cell migration and inflammatory responses in mammalian epithelial tissues. How these events are coordinated to promote wound repair is not understood. We show that p120 catenin regulates the intrinsic migratory properties of primary mouse keratinocytes, but also influences the migratory behavior of neighboring cells by secreted signals. These events are rooted in the ability of p120-catenin to regulate RhoA GTPase activity, which leads to a two-tiered control of cell migration. One restrains cell motility via an increase in actin stress fibers, reduction in integrin turnover and an increase in the robustness of focal adhesions. The other is coupled to the secretion of inflammatory cytokines including interleukin-24, which causally enhances randomized cell movements. Taken together, our results indicate that p120-RhoA-GTPase-mediated signaling can differentially regulate the migratory behavior of epidermal cells, which has potential implications for chronic wound responses and cancer. Synopsis The adherens junction protein p120-catenin differentially regulates the migratory behavior of primary epidermal cells via RhoA-GTPase-mediated signaling. Loss of p120-catenin restricts single cell migration intrinsically and at the same time increases the migratory behavior of neighboring cells during wound repair. Loss of p120-catenin decreases cell migration in single primary epidermal cells as a consequence of increased actin stress fibers, focal adhesion robustness and reduced integrin turnover. The restrain in cell motility is counteracted by the secretion of inflammatory factors to the environment, including IL-24, which enhances the migration of neighboring epidermal cells. The adherens junction protein p120-catenin differentially regulates the migratory behavior of primary epidermal cells via RhoA-GTPase-mediated signaling. Loss of p120-catenin restricts single cell migration intrinsically and at the same time increases the migratory behavior of neighboring cells during wound repair. © 2014 The Authors. Source

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