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A signature of six genes highlights defects on cell growth and specific metabolic pathways in murine and human hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC) represents a major health problem as it afflicts an increasing number of patients worldwide. Albeit most of the risk factors for HCC are known, this is a deadly syndrome with a life expectancy at the time of diagnosis of less than 1 year. Definition of the molecular principles governing the neoplastic transformation of the liver is an urgent need to facilitate the clinical management of patients, based on innovative methods to detect the disease in its early stages and on more efficient therapies. In the present study, we have combined the analysis of a murine model and human samples of HCC to identify genes differentially expressed early in the process of hepatocarcinogenesis, using a microarray-based approach. Expression of 190 genes was impaired in murine HCC from which 65 were further validated by low-density array real-time polymerase chain reaction (RT-PCR). The expression of the best 45 genes was then investigated in human samples resulting in 18 genes in which expression was significantly modified in HCC. Among them, JUN, methionine adenosyltransferase 1A and 2A, phosphoglucomutase 1, and acyl CoA dehydrogenase short/branched chain indicate defective cell proliferation as well as one carbon pathway, glucose and fatty acid metabolism, both in HCC and cirrhotic liver, a well-known preneoplastic condition. These alterations were further confirmed in public transcriptomic datasets from other authors. In addition, vasodilator-stimulated phosphoprotein, an actin-associated protein involved in cytoskeleton remodeling, was also found to be increased in the liver and serum of cirrhotic and HCC patients. In addition to revealing the impairment of central metabolic pathways for liver homeostasis, further studies may probe the potential value of the reported genes for the early detection of HCC.

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Abbreviations

SAM:

S-Adenosylmethionine

MAT1A:

Methionine adenosyltransferase 1A

MAT2A:

Methionine adenosyltransferase 2A

PGM1:

Phosphoglucomutase 1

ACADSB:

Acyl CoA dehydrogenase short/branched chain

ApoA1:

Apolipoprotein A1

C6:

Complement component 6

ALB:

Albumin

CD14:

Monocyte differentiation antigen CD14

PRDX6:

Peroxiredoxin 6

EDNRB:

Endothelin receptor type B

CA3:

Carbonic anhydrase 3

OAT:

Ornithine aminotransferase

SORD:

Sorbitol dehydrogenase

ACAT2:

Acetyl-Coenzyme A acetyltransferase 2

PAH:

Phenylalanine hydroxylase

CBS:

Cystathionine beta-synthase

VASP:

Vasodilator-stimulated phosphoprotein

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Acknowledgments

The technical assistance of Lourdes Ortiz, Virginia Villar, and María I. Mora is acknowledged. This work was supported by the agreement between FIMA and the “UTE project CIMA”; grants Plan Nacional I+D+I SAF2008-0154 from Ministerio de Ciencia e Innovación to FJC; ISCIII-RETIC RD06/0020 to FJC. PS was founded by the ISCIII.

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Authors and Affiliations

  1. Division of Hepatology and Gene Therapy, Proteomics, Genomics & Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, 31008, Pamplona, Spain

    Paul C. Schröder, Víctor Segura, José Ignacio Riezu, Jesús Prieto, Enrique Santamaría & Fernando J. Corrales

  2. Liver Unit, Department of Internal Medicine, University Hospital of Navarra, Pamplona, Spain

    Bruno Sangro

  3. Center for Cooperative Research in Biosciences (CIC) bioGUNE, Bilbao, Bizkaia, Spain

    José M. Mato

  4. Division of Hepatology and Gene Therapy, CIMA, Faculty of Medicine, University of Navarra, 31008, Pamplona, Spain

    Fernando J. Corrales

  5. Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBERehd) https://www.ciberehd.org/

    Bruno Sangro & Jesús Prieto

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  1. Paul C. Schröder
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  2. Víctor Segura
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Schröder, P.C., Segura, V., Riezu, J.I. et al. A signature of six genes highlights defects on cell growth and specific metabolic pathways in murine and human hepatocellular carcinoma. Funct Integr Genomics 11, 419–429 (2011). https://doi.org/10.1007/s10142-011-0230-7

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