Advances in Gastric Cancer Management: Signaling Pathways, Emerging Diagnostic and Therapeutic Strategies.

Influence of the TNF-α gene polymorphism - 308 G/A in the development of chronic gastritis and gastric cancer.

p27kip1 Deficiency Confers Susceptibility to Gastric Carcinogenesis in Helicobacter pylori–Infected Mice

Regulation of Gastric Carcinogenesis by InflammatoryCytokines.

Helicobacter pylori is an important risk factor of gastric cancer (GC). Although many H. pylori virulence factors have been reported, the pathogenic mechanism by which H. pylori infection causes GC remains unclear. The aims of this study were to identify GC-related antigens from H. pylori and characterize their roles in the development of GC. As GC and duodenal ulcer (DU) are considered clinically divergent, we compared two-dimensional immunoblots of an acid-glycine extract of H. pylori probed with serum samples from 15 patients with GC and 15 with DU to find GC-related antigens, which were subsequently identified by mass spectrometry. Many protein spots were recognized by more than one serum, and 24 of these were better recognized by GC sera. The proteins showing higher frequency of recognition in GC group are threonine synthase, rod shape-determining protein, S-adenosylmethionine synthetase, peptide chain release factor 1, DNA-directed RNA polymerase alpha subunit, co-chaperonin GroES (monomeric and dimeric forms), response regulator OmpR, and membrane fusion protein. Of these proteins, GroES was identified as a dominant GC-related antigen with a much higher seropositivity of GC samples (64.2%, n = 95) compared with 30.9% for gastritis (n = 94) and 35.5% for DU (n = 124). GroES seropositivity was more commonly associated with antral GC than with non-antral GC (odds ratio = 2.7; 95% confidence interval, 1.1-6.7). In peripheral blood mononuclear cells, GroES stimulated production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor, IL-1beta, tumor necrosis factor-alpha, cyclooxygenase-2, and prostaglandin E(2). Moreover when incubated with gastric epithelial cells, GroES induced expression of IL-8, cell proliferation, and up-regulation of c-jun, c-fos, and cyclin D1 but caused down-regulation of p27(Kip1). We conclude that GroES of H. pylori is a novel GC-associated virulence factor and may contribute to gastric carcinogenesis via induction of inflammation and promotion of cell proliferation.

Helicobacter pylori is a human pathogen that infects the stomach. More than half of the human population is infected with H. pylori, which is major cause of peptic ulcers, gastric cancers and mucosa-associated lymphoid tissue lymphoma. However, the majority of patients infected with H. pylori generally remain asymptomatic and never develop significant disease. H. pylori has high genetic diversity, and different genotypes of H. pylori are involved in different gastroduodenal disorders. The hosts’ genetic factors also influence the development of peptic ulcers and gastric cancer, and plenty of evidence has demonstrated that genetics plays a role in susceptibility and contributes to the differences between those who develop H. pylori infection, peptic ulcers and gastric cancer.1–3 Numerous single nucleotide polymorphism (SNP) studies have been undertaken to identify candidate genes that most likely play a role in the development of peptic ulcers and gastric cancer.4–8 Recently, a genome wide association study (GWAS) and next generation sequencing study identified several genetic loci that confer susceptibility for H. pylori infection and gastroduodenal disease.9,10 H. pylori prevalence is as high as 90% in some countries, but approximately 5% to 10% of a given population is never infected with H. pylori, even in the presence of high exposure rates.9 A GWAS meta-analysis identified an association between Toll-like receptor 1 (TLR1) and H. pylori seroprevalence, suggesting that genetic variations in TLR1 may explain some of the observed variations in individual risk for developing H. pylori infection.9 The pathogenesis of different clinical outcomes is multifactorial and includes the virulence of H. pylori, environmental factors and host factors. Different types of H. pylori virulence factors (CagA, VacA1, babA2, and OipA) result in different prevalence rates of gastroduodenal disease in different geographic areas. Genetic polymorphisms in the hosts’ interleukin (IL)-10, tumor necrosis factor α (TNF-α), IL-IB and IL-1RN genes have served as important candidates.3–8 IL-10 is an anti-inflammatory cytokine that downregulates cell-mediated immune responses and cytotoxic inflammatory responses. An IL-10 promoter polymorphism is associated with an increased risk of developing a peptic ulcer and gastric cancer. A hallmark of H. pylori-triggered mucosal inflammation is the continuous recruitment of neutrophils and mononuclear cells to the gastric lamina propria. TNF-α plays a crucial role in the host’s immunological defense against H. pylori infection. A TNF-α promoter SNP has been shown to be associated with an increased risk for the development of atrophic gastritis, peptic ulcers and gastric cancer. While the TNF-α 1031 and 863 promoter SNPs are significant risk factors for peptic ulcer in combination with H. pylori infection in Taiwan,1 neither TNF-α 1031 nor 308 TNF-α is a risk factor for peptic ulcer after H. pylori infection in the Polish population.10 In China, IL-B-511, IL-RN, and TNF-α 308 polymorphisms are not associated with the development of duodenal ulcers.8 In Israel, the H. pylori iceA1 bacterial strain is associated with duodenal disease in children, and a TNF-α 238 G polymorphism has been found to be a risk factor for the development of peptic ulcers in children infected with H. pylori.5 In Japan, polymorphisms in interferon-α, rather than IL-1β, are associated with an increased risk of developing gastric ulcers and cancer.4 A GWAS that compared samples form duodenal ulcers and healthy controls in Japan identified two susceptible loci at the prostate stem cell antigen gene at the 8q24 and a locus at the ABO blood group gene at 9q34.11 In Korea, several studies have been undertaken to determine the role of polymorphisms in the IL-10 and TNF-α promoter genes in the development of peptic ulcers and gastric cancer. The IL-10-1082/592 and TNF-α 308 genetic polymorphisms were not found to be important risk factors for peptic ulcers and gastric cancer in Korea.6 However, genetic polymorphisms in IL-1B and IL-1RN contribute to the development of gastric ulcers and gastric cancer after H. pylori infection.7 H. pylori is a strong risk factor for gastric cancer. However, only a small portion of H. pylori-infected subjects eventually develop gastric cancer. Gastric carcinogenesis is affected by several factors, including the strain of H. pylori, environmental factors (smoking, high salt intake, and so forth) and host genetics. IL-10 polymorphisms (819C and 592C alleles have complete linkage disequilibrium with 819T) are associated with H. pylori infection and smoking, which increase the risk of developing noncardia gastric cancer, especially intestinal type, in Korea.3 In conclusion, host genetic polymorphisms, investigating currently known SNPs, the virulence of H. pylori and ethnic and regional differences should be considered when assessing the risk factors for the development of gastric ulcers and cancer.

A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

Hereditary Diffuse Gastric Cancer: Diagnosis and Management

Objective To explore the role and mechanism of Toll-like receptor 4(TLR4) and chemokine receptor 7(CXCR7) in the pathogenesis and development of Helicobacter pylori(HP) positive gastric cancer. Methods Tissues of 147 cases with gastric carcinoma and 60 normal control were collected.The protein expression of TLR4, CXCR7 was detected by immunohistochemical staining.HP infection in these samples were detected by immunohistochemistry and Gram staining. Results The positive rates of TLR4 and CXCR7 in gastric cancer tissues were 63.9% and 62.6%, respectively, which were significantly higher than those in normal control group(15.0% and 5.0%, respectively; χ2=40.832, 56.901, all P<0.01). The positive rates of TLR4 and CXCR7 in patients with lymph node metastasis were significantly higher than those without lymph node metastasis(χ2=9.809, 11.444, all P<0.01). The positive rates of TLR4 and CXCR7 in patients with stage Ⅲ and Ⅳ were significantly higher than those of stageⅠand Ⅱ(χ2=24.927, 27.642, all P<0.01). The expression of TLR4 and CXCR7 in gastric carcinoma was significantly related to HP infection.Kaplan-Meier survival analysis showed that the survival rates in TLR4 and CXCR7 positive group were significantly lower than those in TLR4 and CXCR7 negative groups(F=4.053, 4.091, all P<0.05). COX regression analysis indicated that the TNM stage, the expression of TLR4 and CXCR7 were independent prognosis factors of gastric carcinoma. Conclusion TLR4 and CXCR7 are closely related to the occurrence and development of gastric cancer, and may play an important role in HP carcinogenesis.It may be involved in the invasion and metastasis of gastric cancer cells via LPS/TLR4 signaling pathway. Key words: Stomach neoplasms; Helicobacter pylori; Toll-Like receptor 4; Receptors, chemokine

Helicobacter pylori in gastric cancer: Friend or foe?

Gastric cancer (GC) is one of the global leading causes of cancer death. The association between Helicobacter pylori, which is a predominant risk factor for GC, with GC development has been well-studied. Recently, accumulating evidence has demonstrated the presence of a large population of microorganisms other than H. pylori in the human stomach. Existing sequencing studies have revealed microbial compositional and functional alterations in patients with GC and highlighted a progressive shift in the gastric microbiota in gastric carcinogenesis with marked enrichments of oral or intestinal commensals. Moreover, using a combination of gastric bacterial signatures, GC patients could be significantly distinguished from patients with gastritis. These findings, therefore, emphasize the importance of a collective microbial community in gastric carcinogenesis. Here, we provide an overview of non-H. pylori gastric microbes in gastric carcinogenesis. The molecular mechanisms of gastric microbes-related carcinogenesis and potential clinical applications of gastric microbiota as biomarkers of GC are also explored.

The lipopolysaccharide (LPS) of Helicobacter pylori (HP) is a critical virulence factor in gastric cancer development. As a toxic component of the HP cytoderm, HP LPS causes persistent inflammatory injury to the gastric mucosa. Although HP lipopolysaccharide exhibits weaker endotoxic activity, it still promotes gastric cancer progression by inducing chronic inflammation and enhancing cellular proliferation. However, the specific signaling pathways involved are not fully understood. GES-1, HGC-27, and MKN-45 cells were treated with LPS from HP and E. coli. Western blotting and a luciferase reporter assay were used to analyze MDM2 expression and transcriptional activity. Cell proliferation, migration, and invasion were evaluated through colony formation, scratch wound healing, and transwell assays. Immunohistochemistry was used to examine MDM2 and p53 expression, while immunofluorescence detected regulatory T cells. Gastric cancer mouse models were also used to confirm MDM2's role in gastric cancer. HP infection resulted in elevated MDM2 levels in gastric precancerous lesions and cancers. HP LPS enhances MDM2 expression in GC cells. This effect is mediated through TLR4/MAPK/AP-1, which promotes the proliferation and invasion of gastric cancer cells. In addition, MDM2 participated in Tregs infiltration and promoted the maintenance of an immunosuppressive tumor microenvironment in gastric cancer. HP LPS enhances MDM2 expression in GC cells through the TLR4/MAPK/AP-1 pathway. MDM2 mediates the protumor effects of HP LPS by promoting tumor cell proliferation and regulating Treg-mediated immune suppression. Our study deepens the understanding of gastric cancer progression and identifies MDM2 as an effective therapeutic target.

Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2’s role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/β-catenin phosphorylation. AKT/β-catenin phosphorylation facilitates β-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and β-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/β-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.

Chronic inflammation has been associated with an increased risk of several human malignancies, a classic example being gastric adenocarcinoma (GC). Development of GC is known to result from infection of the gastric mucosa by Helicobacter pylori, which initially induces acute inflammation and, in a subset of patients, progresses over time to chronic inflammation, gastric atrophy, intestinal metaplasia, dysplasia, and finally intestinal-type GC. Germ-line encoded receptors known as pattern-recognition receptors (PRRs) are critical for generating mature pro-inflammatory cytokines that are crucial for both Th1 and Th2 responses. Given that H. pylori is initially targeted by PRRs, it is conceivable that dysfunction within genes of this arm of the immune system could modulate the host response against H. pylori infection, and subsequently influence the emergence of GC. Current evidence suggests that Toll-like receptors (TLRs) (TLR2, TLR3, TLR4, TLR5, and TLR9), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) (NOD1, NOD2, and NLRP3), a C-type lectin receptor (DC-SIGN), and retinoic acid-inducible gene (RIG)-I-like receptors (RIG-I and MDA-5), are involved in both the recognition of H. pylori and gastric carcinogenesis. In addition, polymorphisms in genes involved in the TLR (TLR1, TLR2, TLR4, TLR5, TLR9, and CD14) and NLR (NOD1, NOD2, NLRP3, NLRP12, NLRX1, CASP1, ASC, and CARD8) signaling pathways have been shown to modulate the risk of H. pylori infection, gastric precancerous lesions, and/or GC. Further, the modulation of PRRs has been suggested to suppress H. pylori-induced inflammation and enhance GC cell apoptosis, highlighting their potential relevance in GC therapeutics. In this review, we present current advances in our understanding of the role of the TLR and NLR signaling pathways in the pathogenesis of GC, address the involvement of other recently identified PRRs in GC, and discuss the potential implications of PRRs in GC immunotherapy.

We reported that Rev-erbα, a transcriptional repressor, is reduced in human gastric cancer and that it inhibits glycolysis in cultured gastric cancer cells. However, it is unclear whether Rev-erbα undergoes posttranslational modifications in gastric cancer. Here, we determined levels of Rev-erbα and its posttranslational modifications including phosphorylation, SUMOylation, and ubiquitination in N-methyl-N-nitrosourea (MNU)/Helicobacter pylori (H. pylori)-induced gastric cancer in mice and in cultured human gastric cancer cells. Administration of MNU plus H. pylori infection successfully induced gastric tumor in C57BL/6J mice. MNU/H. pylori decreased the levels of Rev-erbα in gastric tumor tissues of mice accompanied by an increase in the level of lactic acid. Rev-erbα protein SUMOylation and ubiquitination modifications were significantly increased, whereas phosphorylation was unchanged, in gastric cancer cells line BGC-823 and MNU/H. pylori-induced mouse gastric cancer tissues. Using human gastric cancer tissues, we found that Rev-erbα was specifically reduced in mucosal epithelial cells in gastric tissue. Cytokine levels were increased in MNU/H. pylori-exposed mice compared with control mice. Similarly, the levels of IL-6 IL-10, TNF-α, and VEGF were higher in the BGC-823 cell line compared with GES-1 cells. IL-6 and IL-1 incubation did not affect Rev-erbα levels in BGC-823 cells. Furthermore, Rev-erbα was recruited on the promoters of these cytokine genes, which suppressed their expression. Conclusively, Rev-erbα SUMOylation and subsequent ubiquitination may contribute to its protein reduction, which leads to increased glycolysis and abnormal inflammatory responses during the development of gastric cancer. Targeting Rev-erbα and its SUMOylation represents promising approaches for prevention and management of gastric cancer.

Helicobacter pylori (H. pylori) infection is considered a class I carcinogen in the pathogenesis of gastric cancer. In recent years, the interaction relationship between H. pylori infection and autophagy has attracted increasing attention. Most investigators believe that the pathogenesis of gastric cancer is closely related to the formation of an autophagosome-mediated downstream signaling pathway by H. pylori infection-induced cells. Autophagy is involved in H. pylori infection and affects the occurrence and development of gastric cancer. In this paper, the possible mechanism by which H. pylori infection affects autophagy and the progression of related gastric cancer signaling pathways are reviewed.