title: The metabolic gene HAO2 is downregulated in hepatocellular carcinoma and predicts metastasis and poor survival.
abstract: OBJECTIVE
  l-2-Hydroxy acid oxidases are flavin mononucleotide-dependent peroxisomal enzymes, responsible for the oxidation of l-2-hydroxy acids to ketoacids, resulting in the formation of hydrogen peroxide. We investigated the role of HAO2, a member of this family, in rat, mouse and human hepatocarcinogenesis.
  
  
  METHODS
  We evaluated Hao2 expression by qRT-PCR in the following rodent models of hepatocarcinogenesis: the Resistant-Hepatocyte, the CMD and the chronic DENA rat models, and the TCPOBOP/DENA and TCPOBOP only mouse models. Microarray and qRT-PCR analyses were performed on two cohorts of human hepatocellular carcinoma (HCC) patients. Rat HCC cells were transduced by a Hao2 encoding lentiviral vector and grafted in mice.
  
  
  RESULTS
  Downregulation of Hao2 was observed in all investigated rodent models of hepatocarcinogenesis. Interestingly, Hao2 mRNA levels were also profoundly downregulated in early preneoplastic lesions. Moreover, HAO2 mRNA levels were strongly downregulated in two distinct series of human HCCs, when compared to both normal and cirrhotic peri-tumoral liver. HAO2 levels were inversely correlated with grading, overall survival and metastatic ability. Finally, exogenous expression of Hao2 in rat cells impaired their tumorigenic ability.
  
  
  CONCLUSIONS
  Our work identifies for the first time the oncosuppressive role of the metabolic gene Hao2. Indeed, its expression is severely decreased in HCC of different species and etiology, and its reintroduction in HCC cells profoundly impairs tumorigenesis. We also demonstrate that dysregulation of HAO2 is a very early event in the development of HCC and it may represent a useful diagnostic and prognostic marker for human HCC.
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mattu
authors.affiliation: St.Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fornari
authors.affiliation: Institute of Pathology, University Hospital, Basel, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Quagliata
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Perra
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Maria Maddalena
authors.initials: MM
authors.lastname: Angioni
authors.affiliation: University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo (Torino), Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Petrelli
authors.affiliation: University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo (Torino), Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Menegon
authors.affiliation: Department of Experimental and Biomedical Sciences, University of Firenze, Firenze, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morandi
authors.affiliation: Department of Experimental and Biomedical Sciences, University of Firenze, Firenze, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
authors.forename: Giovanna Maria
authors.initials: GM
authors.lastname: Ledda-Columbano
authors.affiliation: St.Orsola-Malpighi University Hospital, Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Gramantieri
authors.affiliation: Institute of Pathology, University Hospital, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo (Torino), Italy. Electronic address: silvia.giordano@unito.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
authors.affiliation: Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. Electronic address: columbano@unica.it.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Columbano
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000502:physiology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000401:mortality / Q000556:secondary*; D015536:Down-Regulation; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000201:enzymology; D008113:Liver Neoplasms / Q000401:mortality / Q000473:pathology*; D008297:Male; D051379:Mice; D060787:Neoplasm Grading; D051381:Rats; D013045:Species Specificity
chemical_list: D000429:Alcohol Oxidoreductases; C408464:HAO2 protein, human; C500896:Hao2 protein, rat
keywords: HCC; Hydroxy acid oxidases; Multistage liver carcinogenesis; TCPOBOP