Fraga, M.F. (Mario F.)
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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.
- Altered expression of adhesion molecules and epithelial-mesenchymal transition in silica-induced rat lung carcinogenesis(Nature Publishing Group, 2004) Saffiotti, U. (Umberto); Vicent, S. (Silvestre); Elizegi, E. (E.); Fraga, M.F. (Mario F.); Pino, I. (Irene); Blanco, D. (Daniel); Montuenga-Badia, L.M. (Luis M.); Esteller, M. (Manel); Lecanda, F. (Fernando)Loss of the epithelial phenotype and disruption of adhesion molecules is a hallmark in the epithelial-mesenchymal transition (EMT) reported in several types of cancer. Most of the studies about the relevance of adhesion and junction molecules in lung cancer have been performed using established tumors or in vitro models. The sequential molecular events leading to EMT during lung cancer progression are still not well understood. We have used a rat model for multistep lung carcinogenesis to study the status of adherens and tight junction proteins and mesenchymal markers during EMT. After silica-induced chronic inflammation, rats sequentially develop epithelial hyperplasia, preneoplastic lesions, and tumors such as adenocarcinomas and squamous cell carcinomas. In comparison with normal and hyperplastic bronchiolar epithelium and with hyperplastic alveolar type II cells, the expression levels of E-cadherin, alpha-catenin and beta-catenin were significantly reduced in adenomatoid preneoplastic lesions and in late tumors. The loss of E-cadherin in tumors was associated with its promoter hypermethylation. alpha- and beta-catenin dysregulation lead to cytoplasmic accumulation in some carcinomas. No nuclear beta-catenin localization was found at any stage of any preneoplastic or neoplastic lesion. Zonula occludens protein-1 was markedly decreased in 66% of adenocarcinomas and in 100% squamous cell carcinomas. The mesenchymal-associated proteins N-cadherin and vimentin were analyzed as markers for EMT. N-cadherin was de novo expressed in 32% of adenocarcinomas and 33% of squamous cell carcinomas. Vimentin-positive tumor cells were found in 35% of adenocarcinomas and 88% of squamous cell carcinomas. Mesenchymal markers were absent in precursor lesions, both hyperplastic and adenomatoid. The present results show that silica-induced rat lung carcinogenesis is a good model to study EMT in vivo, and also provide in vivo evidence suggesting that the changes in cell-cell adhesion molecules are an early event in lung carcinogenesis, while EMT occurs at a later stage.
- New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling(American Society of Hematology, 2009) Stürzenhofecker, B. (Benjamin); Cogliatti, S. (S.B.); Stein, H. (Harald); Ammerpohl, O. (Ole); Hasenclever, D. (D.); Richter, J. (Julia); Korn, B. (Bernhard); Trümper, L. (Lorenz); Kreuz, M. (Markus); Berger, H. (H.); Rosenwald, A. (Andreas); Drexler, H.G. (Hans G.); Ott, G. (German); Loeffler, M. (Markus); Weber, M. (Michael); Schübeler, D. (Dirk); Bentink, S. (S.); Ballestar, E. (E.); Fraga, M.F. (Mario F.); Bernd, H.W (H.W.); Seifert, M. (Marc); Möller, P. (Peter); Bibikova, M. (Marina); Küppers, R. (Ralf); Klapper, W. (Wolfram); Siebert, R. (Reiner); Barker, D. (D.); Esteller, M. (Manel); Wessendorf, S. (Swen); Wickham, E. (Eliza); Hummel, M. (M.); Rosolowski, M. (Maciej); Schwaenen, C. (Carsten); Hansmann, M.L. (Martin-Leo); Potter, K. (Kathleen N.); Prosper-Cardoso, F. (Felipe); Spang, R. (Rainer); Fan, J.B. (Jian-Bing); Calvanese, V. (V.); Lopez-Serra, L. (Lidia); MacLeod, R.A.F. (Roderick A.F.); Aguirre-Ena, X. (Xabier); Martin-Subero, J.I. (Jose Ignacio)Lymphomas are assumed to originate at different stages of lymphocyte development through chromosomal aberrations. Thus, different lymphomas resemble lymphocytes at distinct differentiation stages and show characteristic morphologic, genetic, and transcriptional features. Here, we have performed a microarray-based DNA methylation profiling of 83 mature aggressive B-cell non-Hodgkin lymphomas (maB-NHLs) characterized for their morphologic, genetic, and transcriptional features, including molecular Burkitt lymphomas and diffuse large B-cell lymphomas. Hierarchic clustering indicated that methylation patterns in maB-NHLs were not strictly associated with morphologic, genetic, or transcriptional features. By supervised analyses, we identified 56 genes de novo methylated in all lymphoma subtypes studied and 22 methylated in a lymphoma subtype–specific manner. Remarkably, the group of genes de novo methylated in all lymphoma subtypes was significantly enriched for polycomb targets in embryonic stem cells. De novo methylated genes in all maB-NHLs studied were expressed at low levels in lymphomas and normal hematopoietic tissues but not in nonhematopoietic tissues. These findings, especially the enrichment for polycomb targets in stem cells, indicate that maB-NHLs with different morphologic, genetic, and transcriptional background share a similar stem cell–like epigenetic pattern. This suggests that maB-NHLs originate from cells with stem cell features or that stemness was acquired during lymphomagenesis by epigenetic remodeling.