Autophagy induced by Helicobacter pylori infection is necessary for gastric cancer stem cell emergence
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ORIGINAL ARTICLE
Autophagy induced by Helicobacter pylori infection is necessary for gastric cancer stem cell emergence Sarah Courtois1 · Maria Haykal1 · Clément Bodineau3,4 · Elodie Sifré1 · Lamia Azzi‑Martin1 · Armelle Ménard1 · Francis Mégraud1,2 · Philippe Lehours1,2 · Raúl V. Durán3 · Christine Varon1 · Emilie Bessède1,2 Received: 20 January 2020 / Accepted: 28 July 2020 © The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2020
Abstract Background The main cause of gastric cancer is the infection by the bacterium Helicobacter pylori which induces a chronic inflammation and an epithelial-to-mesenchymal transition (EMT) leading to the emergence of cells with cancer stem cell (CSC) properties. However, the underlying mechanisms have not been fully characterized. Moreover, H. pylori modulates the host cell autophagic process, but a few studies have investigated the role of this process in tumoral transformation. The aim of this study was to determine whether H. pylori-induced autophagy has a role in CSC emergence. Methods Autophagic flux in response to H. pylori infection was characterized in AGS cell line expressing the tandemtagged mCherry-GFP-LC3 protein and using a ratiometric flow cytometry analysis. Then, AGS and MKN45 cell lines were treated with bafilomycin or chloroquine, two pharmaceutical well-known inhibitors of autophagy, and different EMT and CSC characteristics were analyzed. Results First, a co-expression of the gastric CSC marker CD44 and the autophagic marker LC3 in mice and human stomach tissues infected with H. pylori was observed. Then, we demonstrated in vitro that H. pylori was able to activate the autophagy process with a reduced autophagic flux. Finally, infected cells were treated with autophagy inhibitors, which reduced (i) appearance of mesenchymal phenotypes and migration ability related to EMT and (ii) CD44 expression as well as tumorsphere formation capacities reflecting CSC properties. Conclusion In conclusion, all these data show that H. pylori-induced autophagy is implicated in gastric CSC emergence and could represent an interesting therapeutic target. Keywords Autophagic flux · Epithelial-to-mesenchymal transition · CD44 · Tumorspheres · mTORC1 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10120-020-01118-9) contains supplementary material, which is available to authorized users. * Emilie Bessède emilie.bessede@u‑bordeaux.fr 1
Univ. Bordeaux, INSERM, BaRITOn, U1053, F-33000, Bordeaux, France
2
French National Reference Center for Campylobacters and Helicobacters (CNRCH), University Hospital of Bordeaux, Place Amelie Raba Leon, 33076 Bordeaux, France
3
Centro Andaluz de Biología Molecular Y Medicina Regenerativa‑CABIMER, Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Universidad Pablo de Olavide, Américo Vespucio 24, 41092 Sevilla, Spain
4
Institut Européen de Chimie et Biologie, INSERM U1218, University of Bordeaux, Pessac, France
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