title: A signature of six genes highlights defects on cell growth and specific metabolic pathways in murine and human hepatocellular carcinoma.
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.
authors.affiliation: Division of Hepatology and Gene Therapy, Proteomics, Genomics & Bioinformatics Unit, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Schröder
authors.forename: Víctor
authors.initials: V
authors.lastname: Segura
authors.forename: José Ignacio
authors.initials: JI
authors.lastname: Riezu
authors.forename: Bruno
authors.initials: B
authors.lastname: Sangro
authors.forename: José M
authors.initials: JM
authors.lastname: Mato
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Enrique
authors.initials: E
authors.lastname: Santamaría
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Corrales
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D015815:Cell Adhesion Molecules / Q000097:blood; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D055786:Gene Knockout Techniques; D052138:Genes, Neoplasm; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008716:Methionine Adenosyltransferase / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000097:blood; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010750:Phosphoproteins / Q000097:blood; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase