Diagnostic area
MOLECULAR MARKERS OF HEPATOCELLULAR CARCINOMA (HCC) AND THEIR APPLICATIONS
Hepatocellular carcinoma (HCC), also known as malignant hepatoma, is the neoplasic disease with the fifth highest incidence and the third cause of cancer death, with over 500.000 new cases diagnosed every year. Although the main causes of HCC are well-known, the prognosis of patients is bad due to the aggressiveness of the lesion and the lack of effective therapies. The only proven potentially curative therapy for HCC remains surgical, either hepatic resection or liver transplantation, but unfortunately not always it is possible and recurrence of HCC is common. In order to reduce the morbidity and mortality of HCC, the identification of biological markers leading to an earlier diagnosis of the disease is considered one of the priorities in clinical hepatology.
S-adenosylmethionine arises as a central molecule in the preservation of liver homeostasis as a chronic hepatic deficiency results in spontaneous development of steatohepatitis and hepatocellular carcinoma. Methionine adenosyltransferase (MAT) catalyzes the only known AdoMet biosynthetic reaction using methionine and ATP as substrates. In mammalian tissues two distinct genes, MAT1A and MAT2A, encode three different MAT isoforms. The expression of MAT1A is restricted to liver and pancreas.
In the present work, we have attempted a comprehensive analysis of proteins associated with hepatocarcinogenesis in MAT1A knock out mice using a combination of two dimensional electrophoresis and mass spectrometry, to then apply the resulting information to identify hallmarks of human HCC. Our results suggest the existence of individual-specific factors that might condition the development of preneoplastic lesions. Proteomic analysis allowed the identification of 151 differential proteins in MAT1A-/- mice tumors. Among all differential proteins, 27 changed in at least 50% of the analyzed tumors, and some of these alterations were already detected months before the development of HCC in the KO liver. The expression level of genes coding for 13 of these proteins was markedly decreased in human HCC. Interestingly, 7 of these genes were also found to be down-regulated in a pretumoral condition such as cirrhosis, while depletion of only one marker was assessed in less severe liver disorders. Therefore, the improvement of our knowledge about the molecular pathogenesis of HCC and the identification of biomarkers leading to an early diagnosis are of great interest.
Figure 1. Proteome heterogeneity in liver tumors of MAT1A-/- mice. Variability values (defined as the ratio differential spots/analyzed spots x 100) between the 2-DE profiles from normal liver and tumors were analyzed. Gel maps from 2 and 10 mm neoplastic lesions from the same or different animals were compared. Tumor excised from the same liver (black) showed a positive correlation between tumor size and variability. The analysis of tumors from different mice (white) showed variability values 10-fold higher than those found in the WT group.
Table 1. Proteins differentially expressed in at least 50% of MAT1A-/- liver tumors. Proteins already altered in 1 day and 8 month old mice are indicated in red colour and red colour underlined respectively.
