Abstract
Several researchers have analyzed the alterations of the methionine cycle associated with liver disease to clarify the pathogenesis of human hepatocellular carcinoma (HCC) and improve the preventive and the therapeutic approaches to this tumor. Different alterations of the methionine cycle leading to a decrease of S-adenosylmethionine (SAM) occur in hepatitis, liver steatosis, liver cirrhosis, and HCC. The reproduction of these changes in MAT1A-KO mice, prone to develop hepatitis and HCC, demonstrates the pathogenetic role of MAT1A gene under-regulation associated with up-regulation of the MAT2A gene (MAT1A:MAT2A switch), encoding the SAM synthesizing enzymes, methyladenosyltransferase I/III (MATI/III) and methyladenosyltransferase II (MATII), respectively. This leads to a rise of MATII, inhibited by the reaction product, with a consequent decrease of SAM synthesis. Attempts to increase the SAM pool by injecting exogenous SAM have beneficial effects in experimental alcoholic and non-alcoholic steatohepatitis and hepatocarcinogenesis. Mechanisms involved in hepatocarcinogenesis inhibition by SAM include: (1) antioxidative effects due to inhibition of nitric oxide (NO•) production, a rise in reduced glutathione (GSH) synthesis, stabilization of the DNA repair protein Apurinic/Apyrimidinic Endonuclease 1 (APEX1); (2) inhibition of c-myc, H-ras, and K-ras expression, prevention of NF-kB activation, and induction of overexpression of the oncosuppressor PP2A gene; (3) an increase in expression of the ERK inhibitor DUSP1; (4) inhibition of PI3K/AKT expression and down-regulation of C/EBPα and UCA1 gene transcripts; (5) blocking LKB1/AMPK activation; (6) DNA and protein methylation. Different clinical trials have documented curative effects of SAM in alcoholic liver disease. Furthermore, SAM enhances the IFN-α antiviral activity and protects against hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic hepatitis B virus (HBV) infection. However, although SAM prevents experimental tumors, it is not curative against already established experimental and human HCCs. The recent observation that the inhibition of MAT2A and MAT2B expression by miRNAs leads to a rise of endogenous SAM and strong inhibition of cancer cell growth could open new perspectives to the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common human cancer, frequent in areas where the infections by hepatitis B and hepatitis C virus are endemic or food is contaminated by Aflatoxin B1, such as sub-Saharan Africa and far eastern Asia [1,2,3]
The fundamental role of MAT1A downregulation in the pathogenesis of liver injury and HCC was further proved by the demonstration that, in MAT1A-KO mice, chronic SAM deficiency not compensated by MAT2A induction provokes precocious hepatomegaly with macrovesicular steatosis, involving up to 75% of hepatocytes, followed by mononuclear cell infiltration in periportal areas and HCC at eight months of age [59]
SAM and MTA Contribution to Genomic Stability. It is widely accepted [98,99,100] that the interaction of DNA with carcinogens and reactive oxygen and nitrogen species generated during carcinogen metabolism and/or inflammation accompanying early stages of hepatocarcinogenesis results in genomic instability (GI), leading to somatic point mutations, copy number alterations of individual genes, and gain/loss of chromosomal arms
Summary
Hepatocellular carcinoma (HCC) is the fifth most common human cancer, frequent in areas where the infections by hepatitis B and hepatitis C virus are endemic or food is contaminated by Aflatoxin B1, such as sub-Saharan Africa and far eastern Asia [1,2,3]. Therapies with pharmacological agents (i.e., Sorafenib alone or in combination with other signaling inhibitors), trans-arterial chemo-embolization or yttrium-90 microspheres, and percutaneous ethanol injection do not significantly improve the prognosis of patients with advanced disease [2,5,6]. This situation requires new efforts to identify therapies that, combined with traditional treatments, improve their effectiveness. Liver lesions induced by different xenobiotic compounds, including preneoplastic and neoplastic liver lesions, are associated with profound modifications of the methionine metabolism, whose pathogenetic role has been well proved [8]. This review summarizes and discusses the main objectives reached in this field
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