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Traves P.G.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Gomez-Ferreria M.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Aranda A.,Institute Investigaciones Biomedicas Alberto Sols CSIC UAM | Saez G.T.,Hospital General Universitario | And 5 more authors.
PLoS ONE | Year: 2010

Background: The role of thyroid hormones and their receptors (TR) during liver regeneration after partial hepatectomy (PH) was studied using genetic and pharmacologic approaches. Roles in liver regeneration have been suggested for T3, but there is no clear evidence distinguishing the contribution of increased amounts of T3 from the modulation by unoccupied TRs. Methodology/Principal Findings: Mice lacking TRα1/TRβ or TRβ alone fully regenerated liver mass after PH, but showed delayed commitment to the initial round of hepatocyte proliferation and transient but intense apoptosis at 48h post-PH, affecting ∼30% of the remaining hepatocytes. Pharmacologically induced hypothyroidism yielded similar results. Loss of TR activity was associated with enhanced nitrosative stress in the liver remnant, due to an increase in the activity of the nitric oxide synthase (NOS) 2 and 3, caused by a transient decrease in the concentration of asymmetric dimethylarginine (ADMA), a potent NOS inhibitor. This decrease in the ADMA levels was due to the presence of a higher activity of dimethylarginineaminohydrolase-1 (DDAH-1) in the regenerating liver of animals lacking TRα1/TRβ or TRβ. DDAH-1 expression and activity was paralleled by the activity of FXR, a transcription factor involved in liver regeneration and upregulated in the absence of TR. Conclusions/Significance:We report that TRs are not required for liver regeneration; however, hypothyroid mice and TRβ-or TRα1/TRβ- deficient mice exhibit a delay in the restoration of liver mass, suggesting a specific role for TRβ in liver regeneration. Altered regenerative responses are related with a delay in the expression of cyclins D1 and E, and the occurrence of liver apoptosis in the absence of activated TRβ that can be prevented by administration of NOS inhibitors. Taken together, these results indicate that TRβ contributes significantly to the rapid initial round of hepatocyte proliferation following PH, and improves the survival of the regenerating liver at later times. © 2010 Lopez-Fontal et al.


Arriazu E.,Mount Sinai School of Medicine | De Galarreta M.R.,University of Pamplona | Cubero F.J.,RWTH Aachen | Varela-Rey M.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd | And 6 more authors.
Antioxidants and Redox Signaling | Year: 2014

Significance: The extracellular matrix (ECM) is a dynamic microenvironment that undergoes continuous remodeling, particularly during injury and wound healing. Chronic liver injury of many different etiologies such as viral hepatitis, alcohol abuse, drug-induced liver injury, obesity and insulin resistance, metabolic disorders, and autoimmune disease is characterized by excessive deposition of ECM proteins in response to persistent liver damage. Critical Issues: This review describes the main collagenous and noncollagenous components from the ECM that play a significant role in pathological matrix deposition during liver disease. We define how increased myofibroblasts (MF) from different origins are at the forefront of liver fibrosis and how liver cell-specific regulation of the complex scarring process occurs. Recent Advances: Particular attention is paid to the role of cytokines, growth factors, reactive oxygen species, and newly identified matricellular proteins in the regulation of fibrillar type I collagen, a field to which our laboratory has significantly contributed over the years. We compile data from recent literature on the potential mechanisms driving fibrosis resolution such as MF' apoptosis, senescence, and reversal to quiescence. Future Directions: We conclude with a brief description of how epigenetics, an evolving field, can regulate the behavior of MF and of how new "omics" tools may advance our understanding of the mechanisms by which the fibrogenic response to liver injury occurs. © Copyright 2014, Mary Ann Liebert, Inc. 2014.


PubMed | Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd, University of the Basque Country, Basurto University Hospital, Sloan Kettering Cancer Center and 7 more.
Type: | Journal: Methods (San Diego, Calif.) | Year: 2015

Prostate cancer is among the most frequent cancers in men, and despite its high rate of cure, the high number of cases results in an elevated mortality worldwide. Importantly, prostate cancer incidence is dramatically increasing in western societies in the past decades, suggesting that this type of tumor is exquisitely sensitive to lifestyle changes. Prostate cancer frequently exhibits alterations in the PTEN gene (inactivating mutations or gene deletions) or at the protein level (reduced protein expression or altered sub-cellular compartmentalization). The relevance of PTEN in this type of cancer is further supported by the fact that the sole deletion of PTEN in the murine prostate epithelium recapitulates many of the features of the human disease. In order to study the molecular alterations in prostate cancer, we need to overcome the methodological challenges that this tissue imposes. In this review we present protocols and methods, using PTEN as proof of concept, to study different molecular characteristics of prostate cancer.


PubMed | Autonomous University of Madrid, Yale University and Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd
Type: Journal Article | Journal: Antioxidants & redox signaling | Year: 2015

Glutathione (GSH) is the main antioxidant against cell damage. Several pathological states course with reduced nucleophilic tone and perturbation of redox homeostasis due to changes in the 2GSH/GSSG ratio. Here, we investigated the regulation of the rate-limiting GSH biosynthetic heterodimeric enzyme -glutamyl-cysteine ligase (GCL) by microRNAs (miRNAs).In silico analysis of the 3- untranslated regions (UTRs) of both catalytic (GCLc) and regulatory (GCLm) subunits of GCL enabled an identification of miR-433 as a strong candidate for the targeting of GCL. Transitory overexpression of miR-433 in human umbilical vein endothelial cells (HUVEC) showed a downregulation of both GCLc and GCLm in a nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-independent manner. Increases in pro-oxidant stimuli such as exposure to hydrogen peroxide or GSH depletion in endothelial and hepatic cells caused an expected increase in GCLc and GCLm protein expression and abrogation of miR-433 levels, thus supporting a cross-regulation of these pathways. Treatment of HUVEC with miR-433 resulted in reduced antioxidant and redox potentials, increased S-glutathionylation, and reduced endothelial nitric oxide synthase activation. In vivo models of renal and hepatic fibrosis were associated with transforming growth factor 1 (TGF-1)-related reduction of GCLc and GCLm levels that were miR-433 dependent.We describe for the first time an miRNA, miR-433, capable of directly targeting GCL and promoting functional consequences in endothelial physiology and fibrotic processes by decreasing GSH levels.


Ruiz-Extremera A.,University of Granada | Ruiz-Extremera A.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd | Munoz-Gamez J.A.,University of Granada | Salmeron-Ruiz M.A.,La Paz Hospital | And 16 more authors.
Hepatology | Year: 2011

The vertical transmission of hepatitis C virus (HCV-VT) is a major route of HCV infection in children, but the risk factors remain incompletely understood. This study analyzed the role of interleukin 28B (IL28B) in HCV-VT and in the spontaneous clearance of HCV among infected infants. Between 1991 and 2009, 145 mothers were recruited for this study: 100 were HCV-RNA+ve / human immunodeficiency virus negative (HIV-ve), with 128 children, and 33 were HCV-RNA-ve/HCV antibody+ve, with 43 children. The infants were tested for HCV-RNA at birth and at regular intervals until the age of 6 years. IL28B (single nucleotide polymorphism rs12979860) was determined in the mothers and children. HCV-VT was assumed when children presented HCV-RNA+ve in two subsequent blood samples. HCV-VT-infected infants were categorized as: (1) transient viremia with posterior HCV-RNA-ve and without serum-conversion; (2) persistent infection with serum-conversion. Of the 31 mothers with CC polymorphism, 19 (61%) were HCV-RNA+ve, whereas among the 68 mothers with non-CC polymorphism, 56 (82%) were HCV-RNA+ve. In all, 26 of 128 (20%) infants born to the HCV-RNA+ve mothers acquired HCV infection, but only 9 (7%) were chronically infected. The rate of HCV-VT was higher among the mothers with higher HCV viremia. No HCV-VT was detected in the HCV-RNA-ve women. Neither the mothers' nor the childrens' IL-28 status was associated with an increased risk of HCV-VT. The factors influencing viral clearance among the infected children were genotype non-1 and genotype CC of IL28B. In logistic regression, child CC polymorphism was the only predictor of HCV-clearance in HCV genotype-1. Conclusion: High maternal viral load is the only predictive factor of HCV-VT. IL28B plays no role in HCV-VT, but IL28B CC child polymorphism is associated independently with the spontaneous clearance of HCV genotype-1 among infected children. Copyright © 2011 American Association for the Study of Liver Diseases.


Embade N.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd | Fernandez-Ramos D.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd | Varela-Rey M.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd | Beraza N.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd | And 14 more authors.
Hepatology | Year: 2012

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy. © 2011 American Association for the Study of Liver Diseases.


Li J.,University of Southern California | Ramani K.,University of Southern California | Sun Z.,University of Southern California | Zee C.,University of Southern California | And 7 more authors.
American Journal of Pathology | Year: 2010

Methionine adenosyltransferase (MAT) catalyzes the synthesis of S-adenosylmethionine, the principal methyl donor, and is encoded by MAT1A and MAT2A in mammals. Normal liver expresses MAT1A, which is silenced in hepatocellular carcinoma. We have shown that hepatoma cells overexpressing MAT1A grew slower, but whether this is also true in vivo remains unknown. To investigate the effect of overexpressing MAT1A on in vivo tumorigenesis, we generated stable transfectants of Huh7 cells overexpressing either MAT1A or empty vector. Real-time PCR and Western blotting were used to measure expression, and BALB/c nude mice were injected subcutaneously with untransfected or Huh7 cells transfected with empty or MAT1A expression vector to establish tumors. Tumor properties such as proliferation, angiogenesis, and apoptosis were compared, and microarray analysis was performed. Huh7 cells overexpressing MAT1A had higher S-adenosylmethionine levels but lower bromodeoxyuridine incorporation than control cells. Tumor growth rates and weights were lower in MAT1A transfected tumors. In addition, microvessel density and CD31 and Ki-67 staining were lower in MAT1A transfected tumors than control tumors, whereas the apoptosis index was higher in MAT1A-transfected tumors. Forced expression of MAT1A induced genes related to apoptosis and tumor suppression and lowered expression of cell growth and angiogenesis proteins. Our data demonstrate in vivo overexpression of MAT1A in liver cancer cells can suppress tumor growth. They also suggest inducing MAT1A expression might be a strategy to treat hepatocellular carcinoma. Copyright © American Society for Investigative Pathology.


PubMed | Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas Ciberehd, Mayo Medical School, Central South University and Cedars Sinai Medical Center
Type: | Journal: Hepatology (Baltimore, Md.) | Year: 2016

Prohibitin 1 (PHB1) is best known as a mitochondrial chaperone and its role in cancer is conflicting. Mice lacking methionine adenosyltransferase 1 (MAT1) have lower PHB1 expression and we reported c-MYC interacts directly with both proteins. Furthermore, c-MYC and MAT1 expert opposing effects on liver cancer growth, prompting us to examine the interplay between PHB1, MAT1 and c-MYC and PHB1s role in liver tumorigenesis. We found PHB1 is highly expressed in normal hepatocytes and bile duct epithelial cells and down-regulated in most human hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). In HCC and CCA cells, PHB1s expression correlate inversely with growth. PHB1 and MAT1A positively regulate each others expression, whereas PHB1 negatively regulates the expression of c-MYC, MAFG and c-MAF. Both PHB1 and MAT1 heterodimerize with MAX, bind to the E-box element and repress E-box promoter activity. PHB1 promoter contains a repressive E-box element, is occupied mainly by MAX, MNT and MAT1 in nonmalignant cholangiocytes and noncancerous tissues that switched to c-MYC, c-MAF and MAFG in cancer cells and human HCC/CCA. All 8-month old liver-specific Phb1 knockout mice developed HCC and one developed CCA. 5-month old Phb1 heterozygotes but not Phb1 flox mice developed aberrant bile duct proliferation and one developed CCA 3.5 months after left and median bile duct ligation (LMBDL). Phb1 heterozygotes had a more profound fall in the expression of GSH synthetic enzymes and higher hepatic oxidative stress following LMBDL.We have identified PHB1, down-regulated in most human HCC and CCA, heterodimerizes with MAX to repress the E-box. PHB1 positively regulates MAT1A while suppressing c-MYC, MAFG and c-MAF expression. In mice, reduced PHB1 expression predisposes to the development of cholestasis-induced CCA. This article is protected by copyright. All rights reserved.

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