Helicobacter pylori (H. pylori) infection is critical in the development and occurrence of gastric cancer. H. pylori secretes gamma-glutamyl transferase (GGT), which affects energy metabolism and histone methylation in mesenchymal stem cells. However, its effect on human gastric epithelial cells remains unclear. This study aimed to investigate the effects of GGT on energy metabolism and histone methylation in gastric epithelial cells and determine its role in the development and progression of H. pylori-induced gastric cancer. A GGT knockout H. pylori strain and mouse gastric cancer model were constructed, and alpha-ketoglutarate (α-KG) was added. The underlying mechanism was investigated using proteomics, immunohistochemistry, Western blotting, and other experimental assays. H. pylori can colonize the host’s stomach and destroy the gastric epithelium. GGT secreted by H. pylori decreased the concentration of glutamine in the stomach and increased H3K9me3 and H3K27me3 expression, which promoted the proliferation and migration of gastric epithelial cells. Additionally, α-KG reversed this effect. GGT increased the tumorigenic ability of nude mice. GGT, secreted by H. pylori, promoted the expression of ribosomal protein L15 (RPL15), while GGT knockout and supplementation with α-KG and trimethylation inhibitors reduced RPL15 expression and Wnt signaling pathway expression. H. pylori secreted GGT decreased the expression of glutamine and α-KG in gastric epithelial cells, increased the expression of histones H3K9me3 and H3K27me3, and activated the Wnt signaling pathway through RPL15 expression, ultimately changing the biological characteristics of the gastric epithelium and promoting the occurrence of gastric cancer. Altered energy metabolism and histone hypermethylation are important factors involved in this process.

Background It has previously been observed that the prognostic value of tumor size varied according to different stages patients enrolled in gastric cancer. We aimed to investigate the influence of T stage on the prognostic and predicting value of tumor size. Material and methods A total of 13,585 patients with stage I–III gastric cancer were selected from the Surveillance, Epidemiology, and End Results Program (SEER) database. Univariate and multivariate cox regression analysis stratified by T stage were performed. C-index and time-dependent receiver operating characteristic curve (ROC) curve were applied to assess discrimination ability of tumor size and other factors. Nomograms were constructed to further assess the performance of tumor size in a specific model. Calibration ability, discrimination ability, reclassification ability and clinical benefits were executed to judge the performance of models. Results Stratified analyses according to T stage illustrated that with the increase of T stage, the effect of tumor size on overall survival (OS) and cancer-specific survival (CSS) significantly decreased. Moreover, tumor size showed superior discrimination ability in T1 gastric cancer, outperformed other prognostic factors in predicting both CSS (C-index: 0.666, AUC: 0.687) and OS (C-index: 0.635, AUC: 0.660). The cox regression model included tumor size showed better performance than the model excluded tumor size in every aspect. Conclusion T stage had a negative impact on the predicting value of tumor size. Tumor size showed significant prognostic value in T1 gastric cancer, which may be effective in clinical practice.

Abstract Background The impact of Helicobacter pylori (H. pylori) eradication on metabolism of lipid and the potential predictor of such changes remain unclear. Methods This study retrospectively included subjects who underwent at least two 13C urea breath tests between 2015 and 2019 at Wuhan Union Hospital. Based on two H. pylori 13C examination results, subjects were divided into propensity score-matched persistently negative (HPN), persistently positive (HPP), and eradication (HPE) groups. The changes in lipid measurements from before to after H. pylori eradication, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, and triglycerides, were compared within and between groups. Forty-two candidate factors were tested for their ability to predict lipid metabolism changes after H. pylori eradication. Results After propensity score matching, 3412 matched cases were analyzed. Within-group comparisons showed significantly decreased HDL (P < 0.001) and increased LDL (P < 0.001) at the second examination in both the HPE and HPP groups. Between-group comparisons showed that the HDL decrease of the HPE group was significantly larger and smaller when compared with the HPN (P = 0.001) and HPP (P = 0.004) group, respectively. Uni- and multivariate analyses showed that low diastolic blood pressure (DBP) (P = 0.002) and high mean platelet volume (MPV) (P = 0.001) before eradication were associated with increased HDL after eradication. Low total protein (TP) (P < 0.001) was associated with decreased LDL after eradication. Conclusions Compared with sustained H. pylori infectious states, H. pylori eradication alleviated the lipid metabolism deterioration but did not restore it to the uninfected level within 1.5 years after eradication. Patients with low DBP, high MPV, and low TP may reap a greater lipid-metabolism benefit from H. pylori eradication.

Virulence factor gamma-glutamyltransferase (GGT) of H. pylori consumes glutamine (Gln) in the stomach to decrease the tricarboxylic acid metabolite alpha-ketoglutarate (α-kg) and alter the downstream regulation of α-kg as well as cellular biological characteristics. Our previous research indicated that under H. pylori infection, mesenchymal stem cells (MSCs) migrated to the stomach and participated in gastric cancer (GC) development either by differentiating into epithelial cells or promoting angiogenesis. However, how MSCs themselves participate in H. pylori -indicated GC remains unclear. Therefore, a GGT knockout H. pylori strain (Hp-KS-1) was constructed, and downstream histone H3K9 and H3K27 methylation and the PI3K/AKT signaling pathway of α-kg were detected using Western blotting. The biological characteristics of MSCs were also examined. An additive α-kg supplement was also added to H. pylori -treated MSCs to investigate alterations in these aspects. Compared to the control and Hp-KS-1 groups, H. pylori -treated MSCs reduced Gln and α-kg, increased H3K9me3 and H3K27me3, activated the PI3K-AKT signaling pathway, and promoted the proliferation, migration, self-renewal, and pluripotency of MSCs. The addition of α-kg rescued the H. pylori -induced alterations. Injection of MSCs to nude mice resulted in the largest tumors in the H. pylori group and significantly reduced tumor sizes in the Hp-KS-1 and α-kg groups. In summary, GGT of H. pylori affected MSCs by interfering with the metabolite α-kg to increase trimethylation of histone H3K9 and H3K27, activating the PI3K/AKT signaling pathway, and promoting proliferation, migration, self-renewal, and pluripotency in tumorigenesis, elucidating the mechanisms of MSCs in GC development.

Aims: Helicobacter pylori (Hp) infection plays an important role in the development of gastric cancer. Hp can secrete gamma-glutamyltransferase (GGT), however, the impact of GGT of Hp on the human gastric cells is not clear. Although it has been demonstrated that ten-eleven translocation 1 (TET1) is overexpressed in gastric cancer, the relationship between the GGT of Hp and TET1 has not been studied. The aim of this study was to explore the relationship between GGT and TET1, and the role of TET1 in the development of gastric cancer induced by Hp was also explored. Materials and methods: The correlation between TET1 and prognosis of gastric adenoma cancer was analyzed by bioinformatics. The GGT gene of Hp26695 was knocked out by electroporation with plasmid to construct the GGT knockout strain of Hp (Hp-KS-1). The shTET1 lentivirus transfected GES-1, MGC-803 and SGC-7901 cell lines were constructed. The biological characteristics of the three kind of cells were detected. Key findings: TET1 was overexpressed in gastric tissues of Hp infected patients and mice. Bioinformatics analysis showed that in patients with gastric cancer, higher TET1 expression would result in poorer prognosis. The GGT gene of Hp can lead to overexpression of TET1 in GES-1, MGC-803 and SGC-7901 cells, along with the activation of Wnt/beta-catenin signaling pathway, and then promoting tumorigenesis. After silencing TET1, the Wnt/beta-catenin signaling pathway which was activated by GGT of Hp was inhibited. Significance: GGT of Helicobacter pylori can promote gastric carcinogenesis by activating Wnt/beta-catenin signaling pathway trough up-regulating TET1.

BACKGROUND AND STUDY AIMS:Previous studies have identified that colorectal cancer has different fucosylation levels compared to the normal colon. Ulex europaeus agglutinin-I (UEA-I), which specifically combines with α1-2 fucose glycan, is usually used to detect fucosylation levels. Therefore, we used confocal laser endomicroscopy (CLE) to investigate fluorescently labeled UEA-Fluorescein isothiocyanate (FITC) for detecting colonic cancer.PATIENTS AND METHODS:We stained frozen mouse colon tissue sections of normal, adenoma, and adenocarcinoma species with UEA-FITC to detect fucosylation levels in different groups. White light endoscopy and endocytoscopy were first used to detect the lesions. The UEA-FITC was then stained in the mice and human colon tissues in vitro. The CLE was used to detect the UEA-FITC levels of the corresponding lesions, and videos were recorded for quantitation analysis. The diagnostic accuracy of UEA-FITC using CLE was evaluated in terms of sensitivity and specificity.RESULTS:The UEA expression level in colorectal cancer was lower than that in normal intestinal epithelium. The fluorescence intensity ratio of UEA-FITC in colorectal cancer was significantly lower than that in normal tissue detected by CLE in both mice and humans. The combination of UEA-FITC and CLE presented a good diagnostic accuracy with a sensitivity of 95.6% and a specificity of 97.7% for detecting colorectal cancer. The positive and negative predictive values were 91.6% and 95.6%, respectively. Overall, 95.6% of the sites were correctly classified by CLE.CONCLUSIONS:We developed a new imaging strategy to improve the diagnostic efficacy of CLE by using UEA-FITC.