Evidence of origin with epigenetic change of metachronous lesions in early gastric cancer after endoscopic submucosal dissection

Early gastric cancer (EGC) with metachronous lesions developing on scars after endoscopic submucosal dissection (ESD) is extremely rare and hard to treat. We evaluated whether DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase type 1 (CDO1), would predict such lesions. CDO1 methylation (TaqMeth) values were compared between 11 patients with metachronous lesions developing on scars after ESD (M group) identified from 2,055 patients (0.5%) and 33 patients with EGC with no confirmed evidence of metachronous lesions at > 3 years after ESD (solitary [S] group). To assess Helicobacter pylori influence, 11 H. pylori-negative EGC patients (N group) were also analyzed. Each ESD specimen was measured at the tumor (T) and 4-points separated tumor-adjacent noncancerous mucosa (TAM). TaqMeth values for T were significantly higher than TAM (S + M) (P = 0.0019) and TAM (N) (P < 0.0001). Moreover, TAM (M) had significantly higher TaqMeth values than TAM (S) (P < 0.0001) suggesting that TAM (M) exhibited CDO1 hypermethylation similar to T (P = 0.5713). Additionally, TaqMeth values for TAM (S) were significantly higher than TAM (N) (P < 0.0001). The receiver operating characteristic for discriminating the highest TaqMeth values separated TAMs (M) from those of TAMs (S) was 0.81. CDO1 hypermethylation promisingly predicted EGC with metachronous lesions developing on scars after ESD.

The features of metabolic transformations of homocysteine and cysteine in rats’ hepatocytes under the nutritional imbalance

The work is devoted to the study of the homocysteine concentration in blood plasma and the activity of the enzymes of cysteine catabolic transformations γ-glutamate-cysteine ligase and cysteine dioxygenase in rats’ hepatocytes under the conditions of consumption of excessive sucrose content on the background of alimentary protein deprivation. It was found, that the consumption of a high-sucrose diet in animals is accompanied by the increase of homocysteine concentration in plasma by 57% compared to control, whereas the excess of sucrose under the conditions of protein deficiency leads to hypohomocysteinemia (the content of homocysteine decreased by 43% compared to control). The increased plasma homocysteine levels in excess-consuming sucrose can be considered as a prognostic marker of functional disorders of the transsulfuration pathway in the liver and used in the diagnosis of hepatopathologies. Since, the cysteine content in liver cells increased under the conditions of high-sucrose diet consumption, the increasing γ-GCS, a key enzyme of glutathione synthesis, is probably associated with the maintenance of intercellular glutathione stores. Our data of the occurrence hypohomocysteinemia under the conditions of the consumption of excessive amounts of sucrose on the background of dietary protein deficiency highlight gaps in the understanding of the correlation between the metabolic processes of methionine, homocysteine and cysteine in the liver. Under the excessive consumption of sucrose on the background of protein deficiency, the exogenous protein deficiency can be considered as a key factor in reducing the γ-GCS activity (36%) and the cysteine content, because not only the amount of this amino acid is reduced but also its synthesis is disrupted. At the same time, the maximum increase in cysteine dioxygenase activity in rats’ hepatocytes under the conditions of high-sucrose/low-protein diet consumption on the background of decreased γ-GCS activity indicates the utilization of excess cysteine with the formation of taurine and sulfates.

Metabolism of Sulfur-Containing Amino Acids: How the Body Copes with Excess Methionine, Cysteine, and Sulfide

ABSTRACT Metabolism of excess methionine (Met) to homocysteine (Hcy) by transmethylation is facilitated by the expression of methionine adenosyltransferase (MAT) I/III and glycine N-methyltransferase (GNMT) in liver, and a lack of either enzyme results in hypermethioninemia despite normal concentrations of MATII and methyltransferases other than GNMT. The further metabolism of Hcy by the transsulfuration pathway is facilitated by activation of cystathionine β-synthase (CBS) by S-adenosylmethionine (SAM) as well as the relatively high KM of CBS for Hcy. Transmethylation plus transsulfuration effects catabolism of the Met molecule along with transfer of the sulfur atom of Met to serine to synthesize cysteine (Cys). Oxidation and excretion of Met sulfur depend upon Cys catabolism and sulfur oxidation pathways. Excess Cys is oxidized by cysteine dioxygenase 1 (CDO1) and further metabolized to taurine or sulfate. Some Cys is normally metabolized by desulfhydration pathways, and the hydrogen sulfide (H2S) produced is further oxidized to sulfate. If Cys or Hcy concentrations are elevated, Cys or Hcy desulfhydration can result in excess H2S and thiosulfate production. Excess Cys or Met may also promote their limited metabolism by transamination pathways.

Cysteine dioxygenase 1 (CDO1) is differentially expressed in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a leading cause of death in the United States and worldwide (1, 2). We mined published microarray data (3, 4, 5) to discover genes associated with NSCLC. We identified significant differential expression of the gene encoding cysteine dioxygenase 1, CDO1 (6), in tumors from patients with NSCLC. CDO1 may be of relevance to the initiation, progression or maintenance of non-small cell lung cancers.