Helicobacter pylori virulence factor CagA promotes tumorigenesis of gastric cancer via multiple signaling pathways

Abstract Helicobacter pylori, one of the most prevalent human pathogens, colonizes the gastric mucosa and is associated with gastric diseases, such as gastritis and peptic ulcers, and is also a bacterial risk factor for gastric cancer. Cytotoxin-associated gene A (CagA) protein, a major virulence factor of H. pylori, is phosphorylated in cells at its Glu-Pro-IIe-Tyr-Ala (EPIYA) motif and is considered to trigger gastric cancer. CagA is classified into two forms, Western CagA with EPIYA-ABC and East Asian CagA with EPIYA-ABD, with the latter associated with a high risk of developing gastric cancer. CagA causes morphological transformation of cells, yielding the “hummingbird” phenotype in AGS cells and possibly membranous pedestals in the gastric epithelium, albeit rarely. H. pylori adherence to the gastric mucosa is not yet fully understood. Here, we describe an intrafamilial infection case of H. pylori, focusing on the gastric epithelium, H. pylori adherence, and a gene mutation in a child with protein-losing gastroenteropathy (characterized by excessive loss of plasma proteins into the gastrointestinal tract). H. pylori, which also infected family members (mother and father), was genetically a single clone with the virulence genes of an East Asian type. The patient’ gastric mucosa exhibited some unique features. Endoscopy revealed the presence of protein plugs on the mucosal surface, which were immunoelectrophoretically similar to serum proteins. Electron microscopy revealed abnormal gastric epithelial cells, totally covered with the secretions or possessing small swollen structures and irregular microvilli. The patient’s H. pylori infection was characterized by frequently occurring thick pedestals, formed along adherent H. pylori. The serum protein level returned to normal and the protein plugs disappeared after the successful eradication of H. pylori, albeit with lag periods for healing. He had a mutation in the OCRL1 gene, associated with Dent disease (asymptomatic proteinuria). Thus, in the patient’s gastric mucosa, we found the abnormal gastric epithelial cells, which may be caused by an OCRL1 mutation or H. pylori, and pedestal-rich H. pylori infection, possibly caused by a higher level of action of CagA in the abnormal epithelial cells. The data suggests a novel H. pylori virulence factor associated with “excessive plasma protein release”.

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Luteolin exerts an anticancer effect on gastric cancer cells through multiple signaling pathways and regulating miRNAs

Journal of Cancer ◽

10.7150/jca.27183 ◽

2018 ◽

Vol 9 (20) ◽

pp. 3669-3675 ◽

Cited By ~ 4

Author(s):

Yansong Pu ◽

Tao Zhang ◽

Jianhua Wang ◽

Zhijun Mao ◽

Baojun Duan ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Signaling Pathways ◽

Anticancer Effect ◽

Gastric Cancer Cells ◽

Multiple Signaling

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Helicobacter pylori-Mediated Immunity and Signaling Transduction in Gastric Cancer

Journal of Clinical Medicine ◽

10.3390/jcm9113699 ◽

2020 ◽

Vol 9 (11) ◽

pp. 3699

Author(s):

Nozomi Ito ◽

Hironori Tsujimoto ◽

Hideki Ueno ◽

Qian Xie ◽

Nariyoshi Shinomiya

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Cancer Cells ◽

Signaling Pathways ◽

Cancer Progression ◽

Intracellular Signaling ◽

Cellular Proliferation ◽

Gastric Cancer Cells ◽

Downstream Signaling ◽

H Pylori

Helicobacter pylori infection is a leading cause of gastric cancer, which is the second-most common cancer-related death in the world. The chronic inflammatory environment in the gastric mucosal epithelia during H. pylori infection stimulates intracellular signaling pathways, namely inflammatory signals, which may lead to the promotion and progression of cancer cells. We herein report two important signal transduction pathways, the LPS-TLR4 and CagA-MET pathways. Upon H. pylori stimulation, lipopolysaccharide (LPS) binds to toll-like receptor 4 (TLR4) mainly on macrophages and gastric epithelial cells. This induces an inflammatory response in the gastric epithelia to upregulate transcription factors, such as NF-κB, AP-1, and IRFs, all of which contribute to the initiation and progression of gastric cancer cells. Compared with other bacterial LPSs, H. pylori LPS has a unique function of inhibiting the mononuclear cell (MNC)-based production of IL-12 and IFN-γ. While this mechanism reduces the degree of inflammatory reaction of immune cells, it also promotes the survival of gastric cancer cells. The HGF/SF-MET signaling plays a major role in promoting cellular proliferation, motility, migration, survival, and angiogenesis, all of which are essential factors for cancer progression. H. pylori infection may facilitate MET downstream signaling in gastric cancer cells through its CagA protein via phosphorylation-dependent and/or phosphorylation-independent pathways. Other signaling pathways involved in H. pylori infection include EGFR, FAK, and Wnt/β-Catenin. These pathways function in the inflammatory process of gastric epithelial mucosa, as well as the progression of gastric cancer cells. Thus, H. pylori infection-mediated chronic inflammation plays an important role in the development and progression of gastric cancer.

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Lactobacillus plantarum induces apoptosis in gastric cancer cells via modulation of signaling pathways in Helicobacter pylori

Bioimpacts ◽

10.34172/bi.2020.09 ◽

2019 ◽

Vol 10 (2) ◽

pp. 65-72

Author(s):

Hadi Maleki-Kakelar ◽

Jaber Dehghani ◽

Abolfazl Barzegari ◽

Jaleh Barar ◽

Masoud Shirmohamadi ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Signaling Pathways ◽

Lactobacillus Plantarum ◽

Conditioned Media ◽

Dna Ladder ◽

Ags Cells ◽

Immunological Mechanisms ◽

Anti Cancer ◽

H Pylori

Introduction: Gastric cancer is considered the second prevalent cause of death around the world. This type of cancer is generally induced by Helicobacter pylori which could colonize within the gastric mucosa of the infected cases. To date, triple antibiotic therapy has routinely been utilized for controlling the H. pylori-induced infection. However, this strategy has been unsuccessful, in large part because of issues such as occurring point mutations in the H. pylori genome that can induce resistance to the antibiotics administered. Recently, it has been shown that different probiotics may have strong anti-cancer effects, in which they are capable of inhibiting H. pylori by both immunological and non-immunological mechanisms. Here, we aimed at finding possible anti-cancer impacts of the probiotic bacterium Lactobacillus plantarum on gastric cancer, AGS cells. Methods: The anti-cancer effects of the conditioned media of the locally isolated L. plantarum on the AGS cells were evaluated by different analyses such as flow cytometry, DNA ladder assay, DAPI staining, and RT-PCR. Results: Our findings showed that the conditioned media of L. plantarum can inhibit both H. pylori and AGS cells through up-/down-regulation of PTEN, Bax, TLR4, and AKT genes. The exudates of the probiotic L. plantarum bacteria can increase the expression of PTEN, Bax, and TLR4, and also decrease the expression of AKT gene. Conclusion: In agreement with different reports, our results proved the anti-cancer effects of the locally isolated L. plantarum through some immunological cell signaling pathways. Accordingly, it seems the probiotics could be considered as at least a complementary treatment for different types of malignancies.

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Helicobacter pylori-Induced Signaling Pathways Contribute to Intestinal Metaplasia and Gastric Carcinogenesis

BioMed Research International ◽

10.1155/2015/737621 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 18

Author(s):

Soichiro Sue ◽

Wataru Shibata ◽

Shin Maeda

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Atrophic Gastritis ◽

Intestinal Metaplasia ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Gastric Carcinogenesis ◽

Dependent Manner ◽

Intracellular Signaling Pathways ◽

H Pylori

Helicobacter pylori(H. pylori) induces chronic gastric inflammation, atrophic gastritis, intestinal metaplasia, and cancer. Although the risk of gastric cancer increases exponentially with the extent of atrophic gastritis, the precise mechanisms of gastric carcinogenesis have not been fully elucidated.H. pyloriinduces genetic and epigenetic changes in gastric epithelial cells through activating intracellular signaling pathways in a cagPAI-dependent manner.H. pylorieventually induces gastric cancer with chromosomal instability (CIN) or microsatellite instability (MSI), which are classified as two major subtypes of gastric cancer. Elucidation of the precise mechanisms of gastric carcinogenesis will also be important for cancer therapy.

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A Novel Role for Helicobacter pylori Gamma-Glutamyltranspeptidase in Regulating Autophagy and Bacterial Internalization in Human Gastric Cells

Cancers ◽

10.3390/cancers11060801 ◽

2019 ◽

Vol 11 (6) ◽

pp. 801 ◽

Cited By ~ 2

Author(s):

Jimena Bravo ◽

Paula Díaz ◽

Alejandro H. Corvalán ◽

Andrew F.G. Quest

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Virulence Factor ◽

Bacterial Infections ◽

Membrane Integrity ◽

Autophagic Flux ◽

Ags Cells ◽

Gastric Cells ◽

H Pylori

The risk of developing gastric cancer is strongly linked to Helicobacter pylori (H. pylori) infection. Alternatively, autophagy is a conserved response that is important in cellular homeostasis and provides protection against bacterial infections. Although H. pylori is typically considered an extracellular bacterium, several reports indicate that it internalizes, possibly to avoid exposure to antibiotics. Mechanisms by which H. pylori manipulates host cell autophagic processes remain unclear and, importantly, none of the available studies consider a role for the secreted H. pylori virulence factor gamma-glutamyltranspeptidase (HpGGT) in this context. Here, we identify HpGGT as a novel autophagy inhibitor in gastric cells. Our experiments revealed that deletion of HpGGT increased autophagic flux following H. pylori infection of AGS and GES-1 gastric cells. In AGS cells, HpGGT disrupted the late stages of autophagy by preventing degradation in lysosomes without affecting lysosomal acidification. Specifically, HpGGT impaired autophagic flux by disrupting lysosomal membrane integrity, which leads to a decrease in lysosomal cathepsin B activity. Moreover, HpGGT was necessary for efficient internalization of the bacteria into gastric cells. This important role of HpGGT in internalization together with the ability to inhibit autophagy posits HpGGT as a key virulence factor in the development of gastric cancer.

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