Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells

Horvat, Anđela; Noto, Jennifer M.; Ramatchandirin, Balamurugan; Zaika, Elena; Palrasu, Manikandan; Wei, Jinxiong; Schneider, Barbara; El–Rifai, Wael; Peek, Richard M.; Zaika, Alexander

doi:10.1038/s41388-018-0343-8

Cited by 30 publications

(28 citation statements)

References 31 publications

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“…127,128 A recent study revealed that CagA aberrantly promoted the induction of TRIP12 (thyroid hormone receptorinteracting protein 12), an E3 ubiquitin ligase for the p14ARF protein. 129 Therefore, loss of the ARF gene locus as well as the CagA-mediated degradation of the p14ARF protein in gastric epithelial cells may potentiate the p53 degradation induced by CagA.…”

Section: Molecular Structure Of the Caga Proteinmentioning

confidence: 99%

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

2019

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Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer. The cagA gene product, CagA, is delivered into gastric epithelial cells via the bacterial type IV secretion system. Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners. Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks: sustained proliferation, evasion of growth suppressors, invasiveness, resistance to cell death, and genomic instability. Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation. The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation. Since Helicobacter pylori infection triggers a proinflammatory response in host cells, a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa. Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions, the multistep nature of gastric cancer development should include a "hit-and-run" process of CagA action. Thus, acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the "hit-and-run" process of gastric carcinogenesis.

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Section: Molecular Structure Of the Caga Proteinmentioning

confidence: 99%

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

2019

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“…The ubiquitin-proteasomal and autophagylysosomal pathways are crucial for protein homeostasis (26,27). Both systems are altered in H. pylori-infected cells (6,28). To define the mechanism by which H. pylori regulates Siva1, AGS cells were cocultured with H. pylori strain 7.13 or B128, treated with autophagy inhibitor bafilomycin A (100 nM) or proteasomal inhibitor MG132 (20μM) for 4 hours, and analyzed for Siva1 protein.…”

Section: H Pylori Enhances Ubiquitination and Proteasomal Degradatiomentioning

confidence: 99%

“…Using the T4SS, bacteria inject the CagA protein into human gastric cells, where it is phosphorylated by host kinases causing alterations of multiple signaling pathways (3)(4)(5). Several studies pointed out the oncogenic function of CagA (3,5,6). H. pylori also causes strong cellular oxidative and genotoxic stresses, including induction of double strand breaks in DNA (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells

Palrasu¹,

Zaika²,

El–Rifai³

et al. 2020

Journal of Clinical Investigation

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Approximately half of the world's population is infected with the stomach pathogen Helicobacter pylori. Infection with H. pylori is the main risk factor for distal gastric cancer. Bacterial virulence factors, such as the oncoprotein CagA, augment cancer risk. Yet despite high infection rates, only a fraction of H. pylori-infected individuals develop gastric cancer. This raises the question of defining the specific host and bacterial factors responsible for gastric tumorigenesis. To investigate the tumorigenic determinants, we analyzed gastric tissues from human subjects and animals infected with H. pylori bacteria harboring different CagA status. For laboratory studies, well-defined H. pylori strain B128 and its cancerogenic derivative strain 7.13, as well as various bacterial isogenic mutants were employed. We found that H. pylori compromises key tumor suppressor mechanisms: the host stress and apoptotic responses. Our studies showed that CagA induces phosphorylation of XIAP E3 ubiquitin ligase, which enhances ubiquitination and proteasomal degradation of the host proapoptotic factor Siva1. This process is mediated by the PI3K/Akt pathway. Inhibition of Siva1 by H. pylori increases survival of human cells with damaged DNA. It occurs in a strain-specific manner and is associated with the ability to induce gastric tumor.

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“…H pylori may increase the risk for GC by interfering with pathways of tumor suppression. Indeed, Horvat et al showed that H pylori induces ubiquitination and degradation of the tumor suppressor p14ARF, resulting in inhibition of autophagy in gastric cells. The authors demonstrated that H pylori upregulates TRIP12 E3 ubiquitin ligase in vitro, an effect that is mediated by the bacterial virulence factor CagA, and that TRIP12 is also upregulated in the gastric mucosa of H pylori ‐infected patients.…”

Section: Microbial Agents In Gastric Cancermentioning

confidence: 99%

Review: Gastric malignancies: Basic aspects

2019

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Gastric cancer is the third deadliest cancer in the world, and the absolute number of cases is increasing every year due to aging and growing of high‐risk populations. This disease is a consequence of the complex interaction of microbial agents, with environmental and host factors, resulting in the dysregulation of multiple oncogenic and tumor‐suppressing signaling pathways. Despite the advances in our understanding of carcinogenesis, there are still reduced therapeutic options for patients with gastric cancer. In recent years, genomic analyses of gastric tumors have emphasized their molecular heterogeneity. The distinction of gastric cancer molecular subtypes may be a key to identify novel therapeutic targets, to predict patient outcome and response to therapy, and to guide early diagnosis strategies. In this review, we summarize the most recent updates on the relationship between microbial agents and gastric cancer, in particular, Helicobacter pylori, the non‐H pylori microbiome, and Epstein‐Barr virus. We also highlight the main advances made in the past year regarding the molecular characterization of gastric cancer, especially the signatures with potential clinical utility.

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Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells

Cited by 30 publications

References 31 publications

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

Molecular anatomy and pathogenic actions of Helicobacter pylori CagA that underpin gastric carcinogenesis

Bacterial CagA protein compromises tumor suppressor mechanisms in gastric epithelial cells

Review: Gastric malignancies: Basic aspects

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