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Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts.
Vizoso, Miguel; Puig, Marta; Carmona, F Javier; Maqueda, María; Velásquez, Adriana; Gómez, Antonio; Labernadie, Anna; Lugo, Roberto; Gabasa, Marta; Rigat-Brugarolas, Luis G; Trepat, Xavier; Ramírez, Josep; Moran, Sebastian; Vidal, Enrique; Reguart, Noemí; Perera, Alexandre; Esteller, Manel; Alcaraz, Jordi.
Afiliación
  • Vizoso M; Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat 08907, Barcelona, Spain.
  • Puig M; Unit of Biophysics and Bioengineering, School of Medicine, University of Barcelona, Barcelona 08036, Spain, Medical Oncology Department, Hospital Clínic of Barcelona, August Pi i Sunyer Biomedical Institute (IDIBAPS), Barcelona 08036, Spain.
  • Carmona FJ; Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat 08907, Barcelona, Spain.
  • Maqueda M; Department of ESAII, Center for Biomedical Engineering Research, Technical University of Catalonia (UPC), CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona 08028, Spain.
  • Velásquez A; Unit of Biophysics and Bioengineering, School of Medicine, University of Barcelona, Barcelona 08036, Spain.
  • Gómez A; Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat 08907, Barcelona, Spain.
  • Labernadie A; Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain.
  • Lugo R; Unit of Biophysics and Bioengineering, School of Medicine, University of Barcelona, Barcelona 08036, Spain.
  • Gabasa M; Unit of Biophysics and Bioengineering, School of Medicine, University of Barcelona, Barcelona 08036, Spain.
  • Rigat-Brugarolas LG; Department of ESAII, Center for Biomedical Engineering Research, Technical University of Catalonia (UPC), CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona 08028, Spain, Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain.
  • Trepat X; Unit of Biophysics and Bioengineering, School of Medicine, University of Barcelona, Barcelona 08036, Spain, Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain, Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
  • Ramírez J; Servei d'Anatomia Patològica, Hospital Clínic de Barcelona, Barcelona 08036, Spain.
  • Moran S; Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat 08907, Barcelona, Spain.
  • Vidal E; Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat 08907, Barcelona, Spain.
  • Reguart N; Medical Oncology Department, Hospital Clínic of Barcelona, August Pi i Sunyer Biomedical Institute (IDIBAPS), Barcelona 08036, Spain.
  • Perera A; Department of ESAII, Center for Biomedical Engineering Research, Technical University of Catalonia (UPC), CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Barcelona 08028, Spain.
  • Esteller M; Cancer Epigenetics and Biology Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat 08907, Barcelona, Spain, Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain, Department of Physiological Sciences II, School of Medicine, University of L'Hospital
  • Alcaraz J; Unit of Biophysics and Bioengineering, School of Medicine, University of Barcelona, Barcelona 08036, Spain, CIBER de Enfermedades Respiratorias (CIBERES), Madrid, 28029, Spain jalcaraz@ub.edu.
Carcinogenesis ; 36(12): 1453-63, 2015 Dec.
Article en En | MEDLINE | ID: mdl-26449251
Epigenetic changes through altered DNA methylation have been implicated in critical aspects of tumor progression, and have been extensively studied in a variety of cancer types. In contrast, our current knowledge of the aberrant genomic DNA methylation in tumor-associated fibroblasts (TAFs) or other stromal cells that act as critical coconspirators of tumor progression is very scarce. To address this gap of knowledge, we conducted genome-wide DNA methylation profiling on lung TAFs and paired control fibroblasts (CFs) from non-small cell lung cancer patients using the HumanMethylation450 microarray. We found widespread DNA hypomethylation concomitant with focal gain of DNA methylation in TAFs compared to CFs. The aberrant DNA methylation landscape of TAFs had a global impact on gene expression and a selective impact on the TGF-ß pathway. The latter included promoter hypermethylation-associated SMAD3 silencing, which was associated with hyperresponsiveness to exogenous TGF-ß1 in terms of contractility and extracellular matrix deposition. In turn, activation of CFs with exogenous TGF-ß1 partially mimicked the epigenetic alterations observed in TAFs, suggesting that TGF-ß1 may be necessary but not sufficient to elicit such alterations. Moreover, integrated pathway-enrichment analyses of the DNA methylation alterations revealed that a fraction of TAFs may be bone marrow-derived fibrocytes. Finally, survival analyses using DNA methylation and gene expression datasets identified aberrant DNA methylation on the EDARADD promoter sequence as a prognostic factor in non-small cell lung cancer patients. Our findings shed light on the unique origin and molecular alterations underlying the aberrant phenotype of lung TAFs, and identify a stromal biomarker with potential clinical relevance.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Escamosas / Adenocarcinoma / Carcinoma de Pulmón de Células no Pequeñas / Metilación de ADN / Fibroblastos / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans / Male / Middle aged Idioma: En Revista: Carcinogenesis Año: 2015 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Escamosas / Adenocarcinoma / Carcinoma de Pulmón de Células no Pequeñas / Metilación de ADN / Fibroblastos / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans / Male / Middle aged Idioma: En Revista: Carcinogenesis Año: 2015 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido