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Open AccessArticle

Long-Term Helicobacter pylori Infection Switches Gastric Epithelium Reprogramming towards Cancer Stem Cell-Related Differentiation Program in Hp-Activated Gastric Fibroblast-TGFβ Dependent Manner

1
Department of Physiology, The Faculty of Medicine, Jagiellonian University Medical College, 31-531 Cracow, Poland
2
Department of Cell Biology, The Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-837 Cracow, Poland
*
Authors to whom correspondence should be addressed.
Microorganisms 2020, 8(10), 1519; https://doi.org/10.3390/microorganisms8101519
Received: 25 July 2020 / Revised: 23 September 2020 / Accepted: 25 September 2020 / Published: 2 October 2020
(This article belongs to the Section Medical Microbiology)
Helicobacter pylori (Hp)-induced inflammatory reaction leads to a persistent disturbance of gastric mucosa and chronic gastritis evidenced by deregulation of tissue self-renewal and local fibrosis with the crucial role of epithelial–mesenchymal transition (EMT) in this process. As we reported before, Hp activated gastric fibroblasts into cells possessing cancer-associated fibroblast properties (CAFs), which secreted factors responsible for EMT process initiation in normal gastric epithelial RGM1 cells. Here, we showed that the long-term incubation of RGM1 cells in the presence of Hp-activated gastric fibroblast (Hp-AGF) secretome induced their shift towards plastic LGR5+/Oct4high/Sox-2high/c-Mychigh/Klf4low phenotype (l.t.EMT+RGM1 cells), while Hp-non-infected gastric fibroblast (GF) secretome prompted a permanent epithelial–myofibroblast transition (EMyoT) of RGM1 cells favoring LGR/Oct4high/Sox2low/c-Myclow/Klf4high phenotype (l.t.EMTRGM1 cells). TGFβ1 rich secretome from Hp-reprogrammed fibroblasts prompted phenotypic plasticity and EMT of gastric epithelium, inducing pro-neoplastic expansion of post-EMT cells in the presence of low TGFβR1 and TGFβR2 activity. In turn, TGFβR1 activity along with GF-induced TGFβR2 activation in l.t.EMTRGM1 cells prompted their stromal phenotype. Collectively, our data show that infected and non-infected gastric fibroblast secretome induces alternative differentiation programs in gastric epithelium at least partially dependent on TGFβ signaling. Hp infection-activated fibroblasts can switch gastric epithelium microevolution towards cancer stem cell-related differentiation program that can potentially initiate gastric neoplasm. View Full-Text
Keywords: Helicobacter pylori; gastric cancer; activated fibroblasts; cancer associated fibroblasts (CAFs); epithelial–mesenchymal transition (EMT); TGFβ1; cancer stem cells; epithelial–myofibroblast transition Helicobacter pylori; gastric cancer; activated fibroblasts; cancer associated fibroblasts (CAFs); epithelial–mesenchymal transition (EMT); TGFβ1; cancer stem cells; epithelial–myofibroblast transition
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Krzysiek-Maczka, G.; Targosz, A.; Szczyrk, U.; Wrobel, T.; Strzalka, M.; Brzozowski, T.; Czyz, J.; Ptak-Belowska, A. Long-Term Helicobacter pylori Infection Switches Gastric Epithelium Reprogramming towards Cancer Stem Cell-Related Differentiation Program in Hp-Activated Gastric Fibroblast-TGFβ Dependent Manner. Microorganisms 2020, 8, 1519.

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