scholarly journals CagA–ASPP2 complex mediates loss of cell polarity and favors H. pylori colonization of human gastric organoids

2020 ◽  
Vol 117 (5) ◽  
pp. 2645-2655 ◽  
Author(s):  
Ludovico Buti ◽  
Carlos Ruiz-Puig ◽  
Dennis Sangberg ◽  
Thomas M. Leissing ◽  
R. Camille Brewer ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Cell Polarity ◽  
Pathogenic Bacteria ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Transformation ◽  
Gastric Epithelial Cell ◽  
Bacterial Strains ◽  
Mesenchymal Transition ◽  
Infected Cells ◽  
H Pylori

The main risk factor for stomach cancer, the third most common cause of cancer death worldwide, is infection with Helicobacter pylori bacterial strains that inject cytotoxin-associated gene A (CagA). As the first described bacterial oncoprotein, CagA causes gastric epithelial cell transformation by promoting an epithelial-to-mesenchymal transition (EMT)-like phenotype that disrupts junctions and enhances motility and invasiveness of the infected cells. However, the mechanism by which CagA disrupts gastric epithelial cell polarity to achieve its oncogenicity is not fully understood. Here we found that the apoptosis-stimulating protein of p53 2 (ASPP2), a host tumor suppressor and an important CagA target, contributes to the survival of cagA-positive H. pylori in the lumen of infected gastric organoids. Mechanistically, the CagA–ASPP2 interaction is a key event that promotes remodeling of the partitioning-defective (PAR) polarity complex and leads to loss of cell polarity of infected cells. Blockade of cagA-positive H. pylori ASPP2 signaling by inhibitors of the EGFR (epidermal growth factor receptor) signaling pathway—identified by a high-content imaging screen—or by a CagA-binding ASPP2 peptide, prevents the loss of cell polarity and decreases the survival of H. pylori in infected organoids. These findings suggest that maintaining the host cell-polarity barrier would reduce the detrimental consequences of infection by pathogenic bacteria, such as H. pylori, that exploit the epithelial mucosal surface to colonize the host environment.

scholarly journals Consensus transcriptional regulatory networks of coronavirus-infected human cells

2020 ◽  
Vol 7 (1) ◽  
Author(s):  
Scott A. Ochsner ◽  
Rudolf T. Pillich ◽  
Neil J. McKenna
Keyword(s):  
Signaling Pathways ◽  
Regulatory Networks ◽  
Data Exchange ◽  
Epithelial To Mesenchymal Transition ◽  
Transcriptional Regulatory Networks ◽  
Mesenchymal Transition ◽  
Human Genes ◽  
Transcriptional Regulatory ◽  
Infected Cells ◽  
Key Drivers

Abstract Establishing consensus around the transcriptional interface between coronavirus (CoV) infection and human cellular signaling pathways can catalyze the development of novel anti-CoV therapeutics. Here, we used publicly archived transcriptomic datasets to compute consensus regulatory signatures, or consensomes, that rank human genes based on their rates of differential expression in MERS-CoV (MERS), SARS-CoV-1 (SARS1) and SARS-CoV-2 (SARS2)-infected cells. Validating the CoV consensomes, we show that high confidence transcriptional targets (HCTs) of MERS, SARS1 and SARS2 infection intersect with HCTs of signaling pathway nodes with known roles in CoV infection. Among a series of novel use cases, we gather evidence for hypotheses that SARS2 infection efficiently represses E2F family HCTs encoding key drivers of DNA replication and the cell cycle; that progesterone receptor signaling antagonizes SARS2-induced inflammatory signaling in the airway epithelium; and that SARS2 HCTs are enriched for genes involved in epithelial to mesenchymal transition. The CoV infection consensomes and HCT intersection analyses are freely accessible through the Signaling Pathways Project knowledgebase, and as Cytoscape-style networks in the Network Data Exchange repository.

scholarly journals Effect of Astaxanthin on Activation of Autophagy and Inhibition of Apoptosis in Helicobacter pylori-Infected Gastric Epithelial Cell Line AGS

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1750 ◽  
Author(s):  
Hanbit Lee ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Helicobacter Pylori ◽  
Protein Kinase ◽  
Epithelial Cell ◽  
Cell Line ◽  
Gastric Epithelial Cell ◽  
Epithelial Cell Line ◽  
Ags Cells ◽  
Compound C ◽  
H Pylori ◽  
Induced Apoptosis

Helicobacter pylori (H. pylori) infection leads to the massive apoptosis of the gastric epithelial cells, causing gastric ulcers, gastritis, and gastric adenocarcinoma. Autophagy is a cellular recycling process that plays important roles in cell death decisions and can protect cells by preventing apoptosis. Upon the induction of autophagy, the level of the autophagy substrate p62 is reduced and the autophagy-related ratio of microtubule-associated proteins 1A/1B light chain 3B (LC3B)-II/LC3B-I is heightened. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are involved in the regulation of autophagy. Astaxanthin (AST) is a potent anti-oxidant that plays anti-inflammatory and anti-cancer roles in various cells. In the present study, we examined whether AST inhibits H. pylori-induced apoptosis through AMPK-mediated autophagy in the human gastric epithelial cell line AGS (adenocarcinoma gastric) in vitro. In this study, H. pylori induced apoptosis. Compound C, an AMPK inhibitor, enhanced the H. pylori-induced apoptosis of AGS cells. In contrast, metformin, an AMPK activator, suppressed H. pylori-induced apoptosis, showing that AMPK activation inhibits H. pylori-induced apoptosis. AST inhibited H. pylori-induced apoptosis by increasing the phosphorylation of AMPK and decreasing the phosphorylation of RAC-alpha serine/threonine-protein kinase (Akt) and mTOR in H. pylori-stimulated cells. The number of LC3B puncta in H. pylori-stimulated cells increased with AST. These results suggest that AST suppresses the H. pylori-induced apoptosis of AGS cells by inducing autophagy through the activation of AMPK and the downregulation of its downstream target, mTOR. In conclusion, AST may inhibit gastric diseases associated with H. pylori infection by increasing autophagy through the activation of the AMPK pathway.

scholarly journals A Plausible Accelerating Function of Intermediate States in Cancer Metastasis

2019 ◽  
Author(s):  
Hanah Goetz ◽  
Juan R. Melendez-Alvarez ◽  
Luonan Chen ◽  
Xiao-Jun Tian
Keyword(s):  
Tissue Regeneration ◽  
Essential Role ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Transformation ◽  
General Question ◽  
Mesenchymal Transition ◽  
Transition Layers ◽  
Intermediate States ◽  
Statistical Mechanism

AbstractEpithelial-to-mesenchymal transition (EMT) is a fundamental cellular process and plays an essential role in development, tissue regeneration, and cancer metastasis. Interestingly, EMT is not a binary process but instead proceeds with multiple partial intermediate states. However, the functions of these intermediate states are not fully understood. Here, we focus on a general question about how the number of partial EMT states affects cell transformation. First, by fitting a hidden Markov model of EMT with experimental data, we propose a statistical mechanism for EMT in which many unobservable microstates may exist within one of the observable macrostates. Furthermore, we find that increasing the number of intermediate states can accelerate the EMT process and that adding parallel paths or transition layers accelerates the process even further. Last, a stabilized intermediate state traps cells in one partial EMT state. This work advances our understanding of the dynamics and functions of EMT plasticity during cancer metastasis.

scholarly journals SARS-CoV-2 infection induces EMT-like molecular changes, including ZEB1-mediated repression of the viral receptor ACE2, in lung cancer models

2020 ◽  
Author(s):  
C. Allison Stewart ◽  
Carl M. Gay ◽  
Kavya Ramkumar ◽  
Kasey R. Cargill ◽  
Robert J. Cardnell ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Surface Proteins ◽  
Host Cells ◽  
Dependent Manner ◽  
Viral Receptor ◽  
Mesenchymal Transition ◽  
Transcriptional Changes ◽  
Infected Cells ◽  
Potential Strategy

AbstractCOVID-19 is an infectious disease caused by SARS-CoV-2, which enters host cells via the cell surface proteins ACE2 and TMPRSS2. Using normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2. We find that ACE2 expression is restricted to a select population of highly epithelial cells and is repressed by ZEB1, in concert with ZEB1’s established role in promoting epithelial to mesenchymal transition (EMT). Notably, infection of lung cancer cells with SARS-CoV-2 induces metabolic and transcriptional changes consistent with EMT, including upregulation of ZEB1 and AXL, thereby downregulating ACE2 post-infection. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state and lose ACE2 expression, along with its acute respiratory distress syndrome-protective effect, in a ZEB1-dependent manner. AXL-inhibition and ZEB1-reduction, as with bemcentinib, offers a potential strategy to reverse this effect.

scholarly journals Cell transformation disrupts the efficiency of chromosome segregation through microtubule detyrosination

2018 ◽  
Author(s):  
Virginia Silió ◽  
Jonathan B. Millar ◽  
Andrew D. McAinsh
Keyword(s):  
Chromosome Segregation ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Transformation ◽  
Retinal Pigment ◽  
Mesenchymal Cell ◽  
Cell Types ◽  
Retinal Pigment Epithelial Cells ◽  
Mesenchymal Transition ◽  
Carboxypeptidase Inhibitor ◽  
Different Cell Types

The general principles of chromosome segregation are highly conserved throughout eukaryotic evolution. However, it is unknown whether there are differences in spindle or kinetochore composition or architecture which influence the efficiency chromosome segregation in different cell types. Here we show that the transition of human retinal pigment epithelial cells to a mesenchymal phenotype causes a stabilisation of kinetochore-microtubule attachments and an increase in the frequency of chromosome mis-segregation, due to inefficient error-correction, during mitosis. We find that this is caused by microtubule detyrosination during the epithelial-to-mesenchymal transition and that parthenolide, a tubulin carboxypeptidase inhibitor, efficiently reverts mes-enchymal cells to the epithelial mode of chromosome segregation. We propose that reprogramming the post-translational modifications of the mitotic spindle decreases mitotic fidelity and may contribute to CIN in mesenchymal cell populations during tumorigenesis.

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