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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.

SUBMITTER: Negroni L

PROVIDER: S-EPMC4256498 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Integrative quantitative proteomics unveils proteostasis imbalance in human hepatocellular carcinoma developed on nonfibrotic livers.

Negroni Luc L Taouji Said S Arma Daniela D Pallares-Lupon Nestor N Leong Kristen K Beausang Lee Anne LA Latterich Martin M Bossé Roger R Balabaud Charles C Schmitter Jean-Marie JM Bioulac-Sage Paulette P Zucman-Rossi Jessica J Rosenbaum Jean J Chevet Eric E

Molecular & cellular proteomics : MCP 20140915 12

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 ( ...[more]

PMID: 25225353

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Integrative quantitative proteomics unveils proteostasis imbalance in human hepatocellular carcinoma developed on nonfibrotic livers.

Publications

Integrative quantitative proteomics unveils proteostasis imbalance in human hepatocellular carcinoma developed on nonfibrotic livers.

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