title: Oxidation of specific methionine and tryptophan residues of apolipoprotein A-I in hepatocarcinogenesis.
abstract: 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.
authors.affiliation: Division of Hepatology and Gene Therapy, CIMA, Universidad de Navarra, 31008 Pamplona, Spain.
authors.forename: Jokin
authors.initials: J
authors.lastname: Fernández-Irigoyen
authors.forename: Enrique
authors.initials: E
authors.lastname: Santamaría
authors.forename: Laura
authors.initials: L
authors.lastname: Sesma
authors.forename: Javier
authors.initials: J
authors.lastname: Muñoz
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Riezu
authors.forename: Juan
authors.initials: J
authors.lastname: Caballería
authors.forename: Shelly C
authors.initials: SC
authors.lastname: Lu
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Matías A
authors.initials: MA
authors.lastname: Avila
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism; D002853:Chromatography, Liquid; D006509:Hepatitis B / Q000378:metabolism; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism; D013058:Mass Spectrometry; D008715:Methionine / Q000737:chemistry*; D051379:Mice; D009363:Neoplasm Proteins / Q000032:analysis*; D010084:Oxidation-Reduction; D020033:Protein Isoforms / Q000378:metabolism*; D020543:Proteome / Q000032:analysis*; D014364:Tryptophan / Q000737:chemistry*; D015854:Up-Regulation
chemical_list: D016632:Apolipoprotein A-I; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D020543:Proteome; D014364:Tryptophan; D008715:Methionine