Alterations of methionine metabolism in hepatocarcinogenesis: the emergent role of glycine N-methyltransferase in liver injury

Simile, Maria M.; Latte, Gavinella; Feo, Claudio F; Feo, Francesco; Calvisi, Diego F.; Pascale, Rosa M.

doi:10.20524/aog.2018.0288

Cited by 12 publications

(16 citation statements)

References 75 publications

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“…In the serum, Hcy is present mainly in a form that is coupled with albumins and, to a significantly smaller degree, in the form of Hcy or Hcy disulfides coupled with other thiols, e.g., cysteine [22]. Three processes occur as part of Hcy metabolism [22][23][24]:…”

Section: Homocysteinementioning

confidence: 99%

Nutritional Deficiencies, Bariatric Surgery, and Serum Homocysteine Level: Review of Current Literature

Komorniak

Szczuko

Kowalewski³

et al. 2019

OBES SURG

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Obesity is currently one of the biggest global health problems. In the case of severe obesity, bariatric surgeries are considered to be the most important method of treatment. The 2 most commonly performed bariatric surgery procedures include Roux-en-Y gastric bypass and sleeve gastrectomy. However, these methods are not free from complications, and the most common ones (moderately long or long term) are micronutrient deficiencies. The deficiency of vitamins B6, B12, and folic acid as cofactors of the folate cycle contributes to the development of hyperhomocysteinemia. It seems that apart from nutritional factors, there are other aspects that have a significant influence on the concentration of homocysteine in blood, such as the type of conducted bariatric surgery, the post-surgical concentration of betaine and creatinine, and the clearance of methionine (i.e., the mutations of the gene that encodes the MTHFR reductase as well as other genes associated with the process of methylation, e.g., methionine synthase). Their presence might be one of the causes of the increased concentration of homocysteine after surgery despite the fact that patients take vitamin-mineral supplementation.

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Section: Homocysteinementioning

confidence: 99%

Nutritional Deficiencies, Bariatric Surgery, and Serum Homocysteine Level: Review of Current Literature

Komorniak

Szczuko

Kowalewski³

et al. 2019

OBES SURG

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“…These changes were associated with ∼33% and 35% increases in SAM content in HepG2 and Huh7 cells, respectively, whereas the SAH and MTA contents were not significantly modified (Figure 4). In addition, no changes in GNMT expression, another known regulator of SAM level [28], were detected in miR-203 treated cells (Figure 4). Furthermore, miR-203 inhibited BIRC5 (SURVIVIN) and RASAL2 expression (Supplementary Figure 1), thus confirming its suppressor activity for HCC [19, 20].…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, miR-203 transfection induced an increase in the SAM content of transfected cells, probably dependent on the reduction of MAT1A/MAT2A switch, the latter being largely responsible for SAM levels restriction and increase in proliferation capacity of tumor cells [3, 8]. GNMT, a main enzyme in SAM metabolism [28], could also influence the SAM level. However, according to our results, miR-203 transfection did not influence GNMT expression in HepG2 and Huh7 cells.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-203 impacts on the growth, aggressiveness and prognosis of hepatocellular carcinoma by targeting MAT2A and MAT2B genes

et al. 2019

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Hepatocellular carcinoma (HCC) is characterized by the down-regulation of the liver-specific methyladenosyltransferase 1A ( MAT1A ) gene, encoding the S-adenosylmethionine synthesizing isozymes MATI/III, and the up-regulation of the widely expressed methyladenosyltransferase 2A ( MAT2A ), encoding MATII isozyme, and methyladenosyltransferase 2B ( MAT2B ), encoding a β-subunit without catalytic action that regulates MATII enzymatic activity. Different observations showed hepatocarcinogenesis inhibition by miR-203. We found that miR-203 expression in HCCs is inversely correlated with HCC proliferation and aggressiveness markers, and with MAT2A and MAT2B levels. MiR-203 transfection in HepG2 and Huh7 liver cancer cells targeted the 3’-UTR of MAT2A and MAT2B , inhibiting MAT2A and MAT2B mRNA levels and MATα2 and MATβ2 protein expression. These molecular events were paralleled by an increase in SAM content and were associated with growth restraint and apoptosis, inhibition of cell migration and invasiveness, and suppression of the expression of CD133 and LIN28B stemness markers. In contrast, MAT2B transfection in the same cell lines led to a rise of both MATβ2 and MATα2 expression, associated with increases in cell growth, migration, invasion and overexpression of stemness markers and p-AKT. Altogether, our results indicate that the miR-203 oncosuppressor activity may at least partially depend on its inhibition of MAT2A and MAT2B and show, for the first time, an oncogenic activity of MAT2B linked to AKT activation.

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“…The SAM/SAH ratio and the cellular methylation reactions are strongly regulated by GNMT [29]. The latter provides an alternative way for conversion of SAM excess to SAH (Figure 1).…”

Section: Regulatory Mechanisms Of the Methionine Cyclementioning

confidence: 99%

“…The fluctuations in GNMT activity could alter the SAM/SAH ratio, thus influencing the activity of methyltransferases. Furthermore, GNMT, as a major hepatic folate binding protein, binds to and may be inhibited by MTHF [27,28,29,30]. Therefore, when SAM levels increase, MeTHFR inhibition leads to a decrease in free MTHF and a dissociation of the complex GNMT-MTHF (Figure 3) [13,33,34].…”

Section: Regulatory Mechanisms Of the Methionine Cyclementioning

confidence: 99%

Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma

et al. 2019

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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.

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Alterations of methionine metabolism in hepatocarcinogenesis: the emergent role of glycine N-methyltransferase in liver injury

Cited by 12 publications

References 75 publications

Nutritional Deficiencies, Bariatric Surgery, and Serum Homocysteine Level: Review of Current Literature

Nutritional Deficiencies, Bariatric Surgery, and Serum Homocysteine Level: Review of Current Literature

MicroRNA-203 impacts on the growth, aggressiveness and prognosis of hepatocellular carcinoma by targeting MAT2A and MAT2B genes

Alterations of Methionine Metabolism as Potential Targets for the Prevention and Therapy of Hepatocellular Carcinoma

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