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Article

Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions

by
Marina Leite
1,2,3,*,†,
Miguel S. Marques
1,2,†,
Joana Melo
1,2,4,
Marta T. Pinto
1,2,
Bruno Cavadas
1,2,4,
Miguel Aroso
2,5,
Maria Gomez-Lazaro
2,5,
Raquel Seruca
1,2,3 and
Ceu Figueiredo
1,2,3,*
1
Ipatimup–Institute of Molecular Pathology and Immunology of the University of Porto, 4200-135 Porto, Portugal
2
i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal
3
Department of Pathology, Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal
4
ICBAS–Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
5
INEB–Instituto de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2020, 9(2), 513; https://doi.org/10.3390/cells9020513
Submission received: 31 January 2020 / Revised: 20 February 2020 / Accepted: 21 February 2020 / Published: 24 February 2020
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Gastric Cancer)
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Abstract

Helicobacter pylori, a stomach-colonizing Gram-negative bacterium, is the main etiological factor of various gastroduodenal diseases, including gastric adenocarcinoma. By establishing a life-long infection of the gastric mucosa, H. pylori continuously activates host-signaling pathways, in particular those associated with receptor tyrosine kinases. Using two different gastric epithelial cell lines, we show that H. pylori targets the receptor tyrosine kinase EPHA2. For long periods of time post-infection, H. pylori induces EPHA2 protein downregulation without affecting its mRNA levels, an effect preceded by receptor activation via phosphorylation. EPHA2 receptor downregulation occurs via the lysosomal degradation pathway and is independent of the H. pylori virulence factors CagA, VacA, and T4SS. Using small interfering RNA, we show that EPHA2 knockdown affects cell–cell and cell–matrix adhesion, invasion, and angiogenesis, which are critical cellular processes in early gastric lesions and carcinogenesis mediated by the bacteria. This work contributes to the unraveling of the underlying mechanisms of H. pylori–host interactions and associated diseases. Additionally, it raises awareness for potential interference between H. pylori infection and the efficacy of gastric cancer therapies targeting receptors tyrosine kinases, given that infection affects the steady-state levels and dynamics of some receptor tyrosine kinases (RTKs) and their signaling pathways.
Keywords: Helicobacter pylori; EPHA2; receptor tyrosine kinases (RTKs); angiogenesis; invasion; cell–cell adhesion; cell–matrix adhesion; RTK therapy; SRC inhibitors; gastric cancer Helicobacter pylori; EPHA2; receptor tyrosine kinases (RTKs); angiogenesis; invasion; cell–cell adhesion; cell–matrix adhesion; RTK therapy; SRC inhibitors; gastric cancer
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MDPI and ACS Style

Leite, M.; Marques, M.S.; Melo, J.; Pinto, M.T.; Cavadas, B.; Aroso, M.; Gomez-Lazaro, M.; Seruca, R.; Figueiredo, C. Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions. Cells 2020, 9, 513. https://doi.org/10.3390/cells9020513

AMA Style

Leite M, Marques MS, Melo J, Pinto MT, Cavadas B, Aroso M, Gomez-Lazaro M, Seruca R, Figueiredo C. Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions. Cells. 2020; 9(2):513. https://doi.org/10.3390/cells9020513

Chicago/Turabian Style

Leite, Marina, Miguel S. Marques, Joana Melo, Marta T. Pinto, Bruno Cavadas, Miguel Aroso, Maria Gomez-Lazaro, Raquel Seruca, and Ceu Figueiredo. 2020. "Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions" Cells 9, no. 2: 513. https://doi.org/10.3390/cells9020513

APA Style

Leite, M., Marques, M. S., Melo, J., Pinto, M. T., Cavadas, B., Aroso, M., Gomez-Lazaro, M., Seruca, R., & Figueiredo, C. (2020). Helicobacter Pylori Targets the EPHA2 Receptor Tyrosine Kinase in Gastric Cells Modulating Key Cellular Functions. Cells, 9(2), 513. https://doi.org/10.3390/cells9020513

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