title: NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance.
abstract: 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.
authors.affiliation: Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.|Biomedic Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Palermo, Italy.
authors.forename: M R
authors.initials: MR
authors.lastname: Emma
authors.affiliation: INSERM UMR1068, Center of Research in Cancerology of Marseille (CRCM), Marseille, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Iovanna
authors.affiliation: Cancer Research Centre, Hôpital L'Hotel-Dieu de Québec, Centre Hospitalier Universitaire de Québec, Quebec City (Quebec), Canada.|Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec City (Quebec), Canada.
authors.forename: D
authors.initials: D
authors.lastname: Bachvarov
authors.affiliation: Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Histopathology and Immunohistochemistry Laboratory, Palermo, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Puleio
authors.affiliation: Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Histopathology and Immunohistochemistry Laboratory, Palermo, Italy.
authors.forename: G R
authors.initials: GR
authors.lastname: Loria
authors.affiliation: Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.|Biomedic Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Augello
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Candido
authors.affiliation: Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Libra
authors.affiliation: Tumor Immunology Unit, Department of Health Science, University of Palermo, Palermo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gulino
authors.affiliation: Tumor Immunology Unit, Department of Health Science, University of Palermo, Palermo, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cancila
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.|Biomedic Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Palermo, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Montalto
authors.affiliation: Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cervello
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019295:Computational Biology; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D000077157:Sorafenib; D051841:Transcription Factor RelB / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics; D055815:Young Adult
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009536:Niacinamide; D010671:Phenylurea Compounds; D034741:RNA, Small Interfering; D000077157:Sorafenib; D051841:Transcription Factor RelB; C099815:IER3 protein, human; C491643:NUPR1 protein, human; C497593:RELB protein, human