Sesma, L. (Laura)

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2005 - 20104

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    Oxidation of specific methionine and tryptophan residues of apolipoprotein A-I in hepatocarcinogenesis
    (Wiley-VCH Verlag Berlin, 2005) Riezu-Boj, J.I. (José Ignacio); Corrales, F.J. (Fernando José); Lu, S.C. (Shelly C.); Avila, M.A. (Matías Antonio); Fernandez-Irigoyen, J. (Joaquín); Prieto, J. (Jesús); Sesma, L. (Laura); Muñoz, J. (Javier); Caballeria, J. (Juan); Mato, J.M. (José María); Santamaria, E. (Enrique)
    Hepatocellular carcinoma (HCC) is the fifth most common neoplasm with more than 500 000 new cases diagnosed yearly. Although major risk factors of HCC are currently known, the identification of biological targets leading to an early diagnosis of the disease is considered one of the priorities of clinical hepatology. In this work we have used a proteomic approach to identify markers of hepatocarcinogenesis in the serum of a knockout mice deficient in hepatic AdoMet synthesis (MAT1A(-/-)), as well as in patients with HCC. Three isoforms of apolipoprotein A-I (Apo A-I) with different pI were identified in murine serum. Isoform 1 is up-regulated in the serum of MAT1A(-/-) mice much earlier than any histological manifestation of liver disease. Further characterization of the differential isoform by electrospray MS/MS revealed specific oxidation of methionine 85 and 216 to methionine sulfoxide while the sequence of the analogous peptides on isoforms 2 and 3 showed the nonoxidized methionine residues. Enrichment of an acidic isoform of Apo A-I was also assessed in the serum of hepatitis B virus patients who developed HCC. Specific oxidation of methionine 112 to methionine sulfoxide and tryptophans 50 and 108 to formylkinurenine were identified selectively in the up-regulated isoform. Although it is not clear at present whether the occurrence of these modifications has a causal role or simply reflects secondary epiphenomena, this selectively oxidized Apo A-I isoform may be considered as a pathological hallmark that may help to the understanding of the molecular pathogenesis of HCC.
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    Prohibitin deficiency blocks proliferation and induces apoptosis in human hepatoma cells: molecular mechanisms and functional implications
    (Wiley-VCH Verlag Berlin, 2010) Corrales, F.J. (Fernando José); Sanchez-Quiles, V. (Virginia); Prieto, J. (Jesús); Sesma, L. (Laura); Segura, V. (Víctor); Santamaria, E. (Enrique)
    Prohibitin is a multifunctional protein participating in a plethora of essential cellular functions, such as cell signaling, apoptosis, survival and proliferation. In the liver, deficient prohibitin activity participates in the progression of non-alcoholic steatohepatitis and obesity, according to mechanisms that still must be elucidated. In this study, we have used a combination of transcriptomics and proteomics technologies to investigate the response of human hepatoma PLC/PRF/5 cells to prohibitin silencing to define in detail the biological function of hepatic Phb1 and to elucidate potential prohibitin-dependent mechanisms participating in the maintenance of the transformed phenotype. Abrogation of prohibitin reduced proliferation and induced apoptosis in human hepatoma cells in a mechanism dependent on NF kappaB signaling. Moreover, down-regulation of ERp29 together with down-regulation of Erlin 2 suggests ER stress. In agreement, increased C/EBP homologous protein levels, poly-ADP ribose polymerase cleavage and activation of caspase 12 and downstream caspase 7 evidenced ER stress-induced apoptosis. Down-regulation of proteasome activator complex subunit 2 and stathmin as well as accumulation of ubiquitinated proteins suggest interplay between ER stress and proteasome malfunction. Taken together, our results provide evidences for prohibitin having a central role in the maintenance of the transformed and invasive phenotype of human hepatoma cells and may further support previous studies suggesting prohibitin as a potential clinical target.
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    Proteomic analysis of liver diseases: molecular mechanisms and biomarker discovery
    (Bentham Science Publishers, 2008) Corrales, F.J. (Fernando José); Odriozola, L. (Leticia); Fernandez-Irigoyen, J. (Joaquín); Sesma, L. (Laura); Muñoz, J. (Javier); Santamaria, E. (Enrique)
    Liver diseases afflict more than 10% of the world population. Although the main risk factors are known and the population at risk is monitored, new biomarkers are urgently needed to allow early diagnosis and hence more effective therapeutic interventions. Here, we revise the contribution of proteomics to the study of liver diseases and its potential impact in the clinical practice is evaluated.
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    Molecular profiling of hepatocellular carcinoma in mice with a chronic deficiency of hepatic s-adenosylmethionine: relevance in human liver diseases
    (American Chemical Society, 2006) Mora, M.I. (María I.); Corrales, F.J. (Fernando José); Berasain, C. (Carmen); Lu, S.C. (Shelly C.); Avila, M.A. (Matías Antonio); Fernandez-Irigoyen, J. (Joaquín); Prieto, J. (Jesús); Sesma, L. (Laura); Muñoz, J. (Javier); Mato, J.M. (José María); Santamaria, E. (Enrique)
    S-adenosylmethionine arises as a central molecule in the preservation of liver homeostasis as a chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. In the present work, we have attempted a comprehensive analysis of proteins associated with hepatocarcinogenesis in MAT1A knock out mice using a combination of two-dimensional electrophoresis and mass spectrometry, to then apply the resulting information to identify hallmarks of human HCC. Our results suggest the existence of individual-specific factors that might condition the development of preneoplastic lesions. Proteomic analysis allowed the identification of 151 differential proteins in MAT1A-/- mice tumors. Among all differential proteins, 27 changed in at least 50% of the analyzed tumors, and some of these alterations were already detected months before the development of HCC in the KO liver. The expression level of genes coding for 13 of these proteins was markedly decreased in human HCC. Interestingly, seven of these genes were also found to be down-regulated in a pretumoral condition such as cirrhosis, while depletion of only one marker was assessed in less severe liver disorders.