The metabolic gene HAO2 is downregulated in hepatocellular carcinoma and predicts metastasis and poor survival.
- Mattu S Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
- Fornari F St.Orsola-Malpighi University Hospital, Bologna, Italy.
- Quagliata L Institute of Pathology, University Hospital, Basel, Switzerland.
- Perra A Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
- Angioni MM Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
- Petrelli A University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo (Torino), Italy.
- Menegon S University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo (Torino), Italy.
- Morandi A Department of Experimental and Biomedical Sciences, University of Firenze, Firenze, Italy.
- Chiarugi P Department of Experimental and Biomedical Sciences, University of Firenze, Firenze, Italy.
- Ledda-Columbano GM Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
- Gramantieri L St.Orsola-Malpighi University Hospital, Bologna, Italy.
- Terracciano L Institute of Pathology, University Hospital, Basel, Switzerland.
- Giordano S University of Torino School of Medicine, Candiolo Cancer Institute-FPO, IRCCS Candiolo (Torino), Italy. Electronic address: silvia.giordano@unito.it.
- Columbano A Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy. Electronic address: columbano@unica.it.
- 2015-12-15
Published in:
- Journal of hepatology. - 2016
HCC
Hydroxy acid oxidases
Multistage liver carcinogenesis
TCPOBOP
Alcohol Oxidoreductases
Animals
Carcinoma, Hepatocellular
Down-Regulation
Hep G2 Cells
Humans
Liver
Liver Neoplasms
Male
Mice
Neoplasm Grading
Rats
Species Specificity
English
BACKGROUND & AIMS
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.
CONCLUSION
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.
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.
CONCLUSION
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.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1016/j.jhep.2015.11.029
- PMID 26658681
- Persistent URL
- https://sonar.ch/global/documents/160065
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