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NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance.
Emma, M R; Iovanna, J L; Bachvarov, D; Puleio, R; Loria, G R; Augello, G; Candido, S; Libra, M; Gulino, A; Cancila, V; McCubrey, J A; Montalto, G; Cervello, M.
Afiliación
  • Emma MR; Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.
  • Iovanna JL; Biomedic Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Palermo, Italy.
  • Bachvarov D; INSERM UMR1068, Center of Research in Cancerology of Marseille (CRCM), Marseille, France.
  • Puleio R; Cancer Research Centre, Hôpital L'Hotel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, Quebec City (Quebec), Canada.
  • Loria GR; Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec City (Quebec), Canada.
  • Augello G; Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Histopathology and Immunohistochemistry Laboratory, Palermo, Italy.
  • Candido S; Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Histopathology and Immunohistochemistry Laboratory, Palermo, Italy.
  • Libra M; Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.
  • Gulino A; Biomedic Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Palermo, Italy.
  • Cancila V; Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
  • McCubrey JA; Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
  • Montalto G; Tumor Immunology Unit, Department of Health Science, University of Palermo, Palermo, Italy.
  • Cervello M; Tumor Immunology Unit, Department of Health Science, University of Palermo, Palermo, Italy.
Cell Death Dis ; 7(6): e2269, 2016 06 23.
Article en En | MEDLINE | ID: mdl-27336713
Sorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits are modest, and as its mechanisms of action remain elusive, a better understanding of its anticancer effects is needed. Based on our previous study results, we investigated here the implication of the nuclear protein 1 (NUPR1) in HCC and its role in sorafenib treatment. NUPR1 is a stress-inducible protein that is overexpressed in various malignancies, but its role in HCC is not yet fully understood. We found that NUPR1 expression was significantly higher in primary human HCC samples than in the normal liver. Knockdown of NUPR1 significantly increased cell sensitivity to sorafenib and inhibited the cell growth, migration and invasion of HCC cells, both in vitro and in vivo. Moreover, NUPR1 silencing influenced the expression of RELB and IER3 genes. Unsurprisingly, RELB and IER3 knockdown also inhibited HCC cell viability, growth and migration. Using gene expression profiling of HCC cells following stable NUPR1 knockdown, we found that genes functionally involved in cell death and survival, cellular response to therapies, lipid metabolism, cell growth and proliferation, molecular transport and cellular movement were mostly suppressed. Network analysis of dynamic gene expression identified NF-κB and ERK as downregulated gene nodes, and several HCC-related oncogenes were also suppressed. We identified Runt-related transcription factor 2 (RUNX2) gene as a NUPR1-regulated gene and demonstrated that RUNX2 gene silencing inhibits HCC cell viability, growth, migration and increased cell sensitivity to sorafenib. We propose that the NUPR1/RELB/IER3/RUNX2 pathway has a pivotal role in hepatocarcinogenesis. The identification of the NUPR1/RELB/IER3/RUNX2 pathway as a potential therapeutic target may contribute to the development of new treatment strategies for HCC management.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo; Movimiento Celular/efectos de los fármacos; Resistencia a Antineoplásicos/efectos de los fármacos; Neoplasias Hepáticas/patología; Terapia Molecular Dirigida; Proteínas de Neoplasias/metabolismo; Niacinamida/análogos & derivados; Compuestos de Fenilurea/farmacología; Anciano; Anciano de 80 o más Años; Proteínas Reguladoras de la Apoptosis/genética; Proteínas Reguladoras de la Apoptosis/metabolismo; Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética; Carcinoma Hepatocelular/genética; Carcinoma Hepatocelular/patología; Movimiento Celular/genética; Proliferación Celular/efectos de los fármacos; Proliferación Celular/genética; Supervivencia Celular/efectos de los fármacos; Supervivencia Celular/genética; Biología Computacional; Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo; Regulación hacia Abajo/efectos de los fármacos; Femenino; Perfilación de la Expresión Génica; Regulación Neoplásica de la Expresión Génica; Técnicas de Silenciamiento del Gen; Silenciador del Gen/efectos de los fármacos; Humanos; Neoplasias Hepáticas/genética; Masculino; Proteínas de la Membrana/genética; Proteínas de la Membrana/metabolismo; Persona de Mediana Edad; Invasividad Neoplásica; Proteínas de Neoplasias/genética; Niacinamida/farmacología; ARN Interferente Pequeño/metabolismo; Sorafenib; Factor de Transcripción ReIB/genética; Factor de Transcripción ReIB/metabolismo; Transcriptoma/genética; Adulto Joven
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Fenilurea / Movimiento Celular / Niacinamida / Resistencia a Antineoplásicos / Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico / Terapia Molecular Dirigida / Neoplasias Hepáticas / Proteínas de Neoplasias Tipo de estudio: Prognostic_studies Límite: Aged80 Idioma: En Revista: Cell Death Dis Año: 2016 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Compuestos de Fenilurea / Movimiento Celular / Niacinamida / Resistencia a Antineoplásicos / Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico / Terapia Molecular Dirigida / Neoplasias Hepáticas / Proteínas de Neoplasias Tipo de estudio: Prognostic_studies Límite: Aged80 Idioma: En Revista: Cell Death Dis Año: 2016 Tipo del documento: Article País de afiliación: Italia Pais de publicación: Reino Unido