title: Integrative quantitative proteomics unveils proteostasis imbalance in human hepatocellular carcinoma developed on nonfibrotic livers.
abstract: Proteomics-based clinical studies represent promising resources for the discovery of novel biomarkers or for unraveling molecular mechanisms underlying particular diseases. Here, we present a discovery study of hepatocellular carcinoma developed on nonfibrotic liver (nfHCC) that combines complementary quantitative iTRAQ-based proteomics and phosphoproteomics approaches. Using both approaches, we compared a set of 24 samples (18 nfHCC versus six nontumor liver tissue). We identified 43 proteins (67 peptides) differentially expressed and 32 peptides differentially phosphorylated between the experimental groups. The functional analysis of the two data sets pointed toward the deregulation of a protein homeostasis (proteostasis) network including the up-regulation of the Endoplasmic Reticulum (ER) resident HSPA5, HSP90B1, PDIA6, and P4HB and of the cytosolic HSPA1B, HSP90AA1, HSPA9, UBC, CNDP2, TXN, and VCP as well as the increased phosphorylation of the ER resident calnexin at Ser583. Antibody-based validation approaches (immunohistochemistry, immunoblot, Alphascreen(®), and AMMP(®)) on independent nfHCC tumor sets (up to 77 samples) confirmed these observations, thereby indicating a common mechanism occurring in nfHCC tumors. Based on these results we propose that adaptation to proteostasis imbalance in nfHCC tumors might confer selective advantages to those tumors. As such, this model could provide an additional therapeutic opportunity for those tumors arising on normal liver by targeting the tumor proteostasis network. Data are available via ProteomeXchange with identifier PXD001253.
authors.affiliation: From the ‡UMR 5248 CNRS-Université Bordeaux-IPB, Bordeaux, France; §Université de Bordeaux, Bordeaux, France;
authors.forename: Luc
authors.initials: L
authors.lastname: Negroni
authors.affiliation: §Université de Bordeaux, Bordeaux, France; ¶INSERM, UMR-U1053, Team ≪ Endoplasmic Reticulum Stress and Cancer ≫, Bordeaux, France. ‖BMYscreen, Bordeaux, France;
authors.forename: Said
authors.initials: S
authors.lastname: Taouji
authors.affiliation: From the ‡UMR 5248 CNRS-Université Bordeaux-IPB, Bordeaux, France; ¶INSERM, UMR-U1053, Team ≪ Endoplasmic Reticulum Stress and Cancer ≫, Bordeaux, France. **INSERM, UMR-U1053, ≪ Repteam ≫, Bordeaux, France;
authors.forename: Daniela
authors.initials: D
authors.lastname: Arma
authors.affiliation: §Université de Bordeaux, Bordeaux, France; ¶INSERM, UMR-U1053, Team ≪ Endoplasmic Reticulum Stress and Cancer ≫, Bordeaux, France.
authors.forename: Nestor
authors.initials: N
authors.lastname: Pallares-Lupon
authors.affiliation: ‡‡BioScale, Inc., 4 Maguire Rd, Lexington, MA 02421, USA;
authors.forename: Kristen
authors.initials: K
authors.lastname: Leong
authors.affiliation: ‡‡BioScale, Inc., 4 Maguire Rd, Lexington, MA 02421, USA;
authors.forename: Lee Anne
authors.initials: LA
authors.lastname: Beausang
authors.affiliation: ‡‡BioScale, Inc., 4 Maguire Rd, Lexington, MA 02421, USA; §§Proteogenomics Research Institute for Systems Medicine, San Diego, California 92121;
authors.forename: Martin
authors.initials: M
authors.lastname: Latterich
authors.affiliation: ¶¶PerkinElmer, Waltham, Massachusetts 02451;
authors.forename: Roger
authors.initials: R
authors.lastname: Bossé
authors.affiliation: §Université de Bordeaux, Bordeaux, France; **INSERM, UMR-U1053, ≪ Repteam ≫, Bordeaux, France;
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.affiliation: From the ‡UMR 5248 CNRS-Université Bordeaux-IPB, Bordeaux, France; §Université de Bordeaux, Bordeaux, France;
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Schmitter
authors.affiliation: §Université de Bordeaux, Bordeaux, France; **INSERM, UMR-U1053, ≪ Repteam ≫, Bordeaux, France;
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.affiliation: ‖‖Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, IUH, Paris, F-75010 France; Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France; Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France; Université Paris Diderot, F-75013 Paris;
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
authors.affiliation: §Université de Bordeaux, Bordeaux, France; **INSERM, UMR-U1053, ≪ Repteam ≫, Bordeaux, France;
authors.forename: Jean
authors.initials: J
authors.lastname: Rosenbaum
authors.affiliation: §Université de Bordeaux, Bordeaux, France; ¶INSERM, UMR-U1053, Team ≪ Endoplasmic Reticulum Stress and Cancer ≫, Bordeaux, France. ‖BMYscreen, Bordeaux, France; Centre Régional de Lutte Contre le Cancer Eugène Marquis, 35000 Rennes, France eric.chevet@inserm.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D037281:Calnexin / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D004150:Dipeptidases / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D000074405:Valosin Containing Protein
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D009363:Neoplasm Proteins; D010750:Phosphoproteins; C491203:TXN protein, human; C440529:UBC antigen; D037281:Calnexin; D013879:Thioredoxins; D011393:Procollagen-Proline Dioxygenase; D004150:Dipeptidases; C031499:CNDP2 protein, human; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C526497:P4HB protein, human; C496931:PDIA6 protein, human; D019704:Protein Disulfide-Isomerases