title: Metallothionein-1 as a biomarker of altered redox metabolism in hepatocellular carcinoma cells exposed to sorafenib.
abstract: Sorafenib, a kinase inhibitor active against various solid tumours, induces oxidative stress and ferroptosis, a new form of oxidative necrosis, in some cancer cells. Clinically-applicable biomarkers that reflect the impact of sorafenib on the redox metabolism of cancer cells are lacking.
  
  
  
  We used gene expression microarrays, real-time PCR, immunoblot, protein-specific ELISA, and gene reporter constructs encoding the enzyme luciferase to study the response of a panel of cancer cells to sorafenib. Tumour explants prepared from surgical hepatocellular carcinoma (HCC) samples and serum samples obtained from HCC patients receiving sorafenib were also used.
  
  
  
  We observed that genes of the metallothionein-1 (MT1) family are induced in the HCC cell line Huh7 exposed to sorafenib. Sorafenib increased the expression of MT1G mRNA in a panel of human cancer cells, an effect that was not observed with eight other clinically-approved kinase inhibitors. We identified the minimal region of the MT1G promoter that confers inducibility by sorafenib to a 133 base pair region containing an Anti-oxidant Response Element (ARE) and showed the essential role of the transcription factor NRF2 (Nuclear factor erythroid 2-Related Factor 2). We examined the clinical relevance of our findings by analysing the regulation of MT1G in five tumour explants prepared from surgical HCC samples. Finally, we showed that the protein levels of MT1 increase in the serum of some HCC patients receiving sorafenib, and found an association with reduced overall survival.
  
  
  
  These findings indicate that MT1 constitute a biomarker adapted for exploring the impact of sorafenib on the redox metabolism of cancer cells.
authors.affiliation: Laboratoire de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Avenue Laennec, 80054, Amiens, Cedex, France.|EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Houessinon
authors.affiliation: EA4294, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: François
authors.affiliation: Laboratoire de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Avenue Laennec, 80054, Amiens, Cedex, France.|EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Sauzay
authors.affiliation: Laboratoire de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Avenue Laennec, 80054, Amiens, Cedex, France.|EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Louandre
authors.affiliation: Centre de Ressources en Biologie Moléculaire, UPJV, Amiens, France.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Mongelard
authors.affiliation: Laboratoire de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Avenue Laennec, 80054, Amiens, Cedex, France.|EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Godin
authors.affiliation: Service de Pharmacologie, CHU Sud, Amiens, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Bodeau
authors.affiliation: Department of clinical laboratory, Tohoku Medical and Pharmaceutical University Hospital, Sendai, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Laboratoire de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Avenue Laennec, 80054, Amiens, Cedex, France.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Saidak
authors.affiliation: Centre de Ressources en Biologie Moléculaire, UPJV, Amiens, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gutierrez
authors.affiliation: Service de Chirurgie Viscérale, CHU Sud, Amiens, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Régimbeau
authors.affiliation: Centre de Ressources Biologiques, Hôpitaux Universitaires Paris Seine-Saint-Denis, APHP, Bondy, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Barget
authors.affiliation: EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Barbare
authors.affiliation: Service d'Hépatologie, Pôle d'Activités Cancérologiques Spécialisées, APHP, Hôpitaux Universitaires Paris Seine-Saint-Denis, Site Jean Verdier, Bondy, France.|Université Paris 13, Sorbonne Paris Cité, UFR SMBH, Bobigny, France.|Inserm UMR-1162, Génomique Fonctionnelle des Tumeurs solides, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ganne
authors.affiliation: EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Chauffert
authors.affiliation: Service de Gastroentérologie et d'Endoscopie, Hôpital Cochin, APHP, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UFR de médecine, Paris, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Coriat
authors.affiliation: Laboratoire de Biochimie, Centre de Biologie Humaine (CBH), CHU Amiens Sud, Avenue Laennec, 80054, Amiens, Cedex, France. Galmiche.Antoine@chu-amiens.fr.|EA4666, Université de Picardie Jules Verne (UPJV), Amiens, France. Galmiche.Antoine@chu-amiens.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Galmiche
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015415:Biomarkers; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D003545:Cysteine / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D008668:Metallothionein / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects*; D018384:Oxidative Stress; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D000077157:Sorafenib; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D008668:Metallothionein; D000077157:Sorafenib; D003545:Cysteine
keywords: Biomarker; Ferroptosis; Hepatocellular carcinoma; Metallothionein-1; Redox metabolism; Sorafenib