Gutiérrez-de-Juan, V. (Virginia)

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2018 - 20203

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    MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
    (Springer Nature, 2018) Fernandez, A. (Agustín); Banales, J.M. (Jesús M.); Villa, E. (Erica); Simon, J. (Jorge); Gutiérrez-de-Juan, V. (Virginia); Berasain, C. (Carmen); Arbelaiz, A. (Ander); Zubiete-Franco, I. (Imanol); Lu, S.C. (Shelly C.); Avila, M.A. (Matías Antonio); Aransay, A.M. (Ana M.); Fraga, M.F. (Mario F.); Beraza, N. (Naiara); Perugorria, M.J. (María J.); Lavín, J.L. (José Luis); Crespo, J. (Javier); Iruzibieta, P. (Paula); Varela-Rey, M. (Marta); Delgado, T.C. (Teresa C.); Barbier-Torres, L. (Lucía); Lopitz-Otsoa, F. (Fernando); Fernández-Ramos, D. (David); Anguita, A. (Ángel); Fernández-Tussy, P. (Pablo); Mato, J.M. (José María); Navasa, N. (Nicolás); Martinez-Chantar, M.L. (María Luz)
    Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)-/- mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2-/- mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.
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    Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis
    (2020) Banales, J.M. (Jesús M.); Simon, J. (Jorge); Elortza, F. (Felix); Gutiérrez-de-Juan, V. (Virginia); Lozano, J.J. (Juan J.); Mercado-Gómez, M. (Maria); Azkargorta, M. (Mikel); Goikoetxea-Usandizaga, N. (Naroa); Avila, M.A. (Matías Antonio); Alonso, C. (Cristina); Arizmendi, J.M. (Jesús M.); Beraza, N. (Naiara); Lachiondo-Ortega, S. (Sofia); Rodríguez-Agudo, R. (Rubén); Delgado, T.C. (Teresa C.); Aloria, K. (Kerman); Lopitz-Otsoa, F. (Fernando); Fernández-Ramos, D. (David); Mayor, U. (Ugo); Barrio, R. (Rosa); Bizkarguenaga, M. (Maider); Mato, J.M. (José María); Sutherland, J.D. (James D.); Martinez-Chantar, M.L. (María Luz); Marin, J.J.G (Jose J.G.); Lectez, B. (Benoît); Serrano-Macia, M. (Marina)
    Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl4)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl4-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.
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    SUMOylation regulates LKB1 localization and its oncogenic activity in liver cancer
    (Elsevier BV, 2019) Villa, E. (Erica); Simon, J. (Jorge); Carlevaris, O. (Onintza); Gutiérrez-de-Juan, V. (Virginia); Díaz-Quintana, A. (Antonio); García-Rodríguez, J.L. (Juan L.); Zubiete-Franco, I. (Imanol); Avila, M.A. (Matías Antonio); Martín, C. (Cesar); Beraza, N. (Naiara); Rodriguez, M. (Manuel); Beguiristain-Gómez, A. (Adolfo); Varela-Rey, M. (Marta); Delgado, T.C. (Teresa C.); Barbier-Torres, L. (Lucía); López-de-Davalillo, S. (Sergio); Lopitz-Otsoa, F. (Fernando); Fernández-Ramos, D. (David); Berra, E. (Edurne); Fernández-Tussy, P. (Pablo); Mato, J.M. (José María); Aspichueta, P. (Patricia); Díaz-Moreno, I. (Irene); Martinez-Chantar, M.L. (María Luz); Calvisi, D.F. (Diego F.); Serrano-Macia, M. (Marina)
    Background: Even though liver kinase B1 (LKB1) is usually described as a tumor suppressor in a wide variety of tissues, it has been shown that LKB1 aberrant expression is associated with bad prognosis in Hepatocellular Carcinoma (HCC). Methods: Herein we have overexpressed LKB1 in human hepatoma cells and by using histidine pull-down assay we have investigated the role of the hypoxia-related post-translational modification of Small Ubiquitin-related Modifier (SUMO)ylation in the regulation of LKB1 oncogenic role. Molecular modelling between LKB1 and its interactors, involved in regulation of LKB1 nucleocytoplasmic shuttling and LKB1 activity, was performed. Finally, high affinity SUMO binding entities-based technology were used to validate our findings in a pre-clinical mouse model and in clinical HCC. Findings: We found that in human hepatoma cells under hypoxic stress, LKB1 overexpression increases cell viability and aggressiveness in association with changes in LKB1 cellular localization. Moreover, by using sitedirected mutagenesis, we have shown that LKB1 is SUMOylated by SUMO-2 at Lys178 hampering LKB1 nucleocytoplasmic shuttling and fueling hepatoma cell growth. Molecular modelling of SUMO modified LKB1 further confirmed steric impedance between SUMOylated LKB1 and the STe20-Related ADaptor cofactor (STRADα), involved in LKB1 export from the nucleus. Finally, we provide evidence that endogenous LKB1 is modified by SUMO in pre-clinical mouse models of HCC and clinical HCC, where LKB1 SUMOylation is higher in fast growing tumors. Interpretation: Overall, SUMO-2 modification of LKB1 at Lys178 mediates LKB1 cellular localization and its oncogenic role in liver cancer.