Cancer Letters

Cancer Letters

Volume 374, Issue 2, 1 May 2016, Pages 292-303
Cancer Letters

Original Articles
Helicobacter pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote cancer stem cell-like properties in human gastric cancer

https://doi.org/10.1016/j.canlet.2016.02.032Get rights and content
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Highlights

  • H. pylori infection induces the emergence of CSC-like properties in gastric cancer cells.

  • H. pylori activates the Wnt/β-catenin signaling pathway in a CagA-dependent manner.

  • Wnt/β-catenin signaling activation is dependent upon the H. pylori-mediated phosphorylation of β-catenin at Ser675 and Ser552 in a c-met- and/or Akt-dependent manner.

  • Wnt/β-catenin signaling activation is responsible for the H. pylori-induced CSC-like properties.

  • H. pylori-activated Wnt/β-catenin signaling promotes the promoter activity of Nanog and Oct4 and upregulates their expression.

Abstract

Helicobacter pylori (H. pylori) infection is considered a major risk factor for gastric cancer. CagA behaves as a major bacterial oncoprotein playing a key role in H. pylori-induced tumorigenesis. Cancer stem cells (CSCs) are believed to possess the ability to initiate tumorigenesis and promote progression. Although studies have suggested that cancer cells can exhibit CSC-like properties in the tumor microenvironment, it remains unclear whether H. pylori infection could induce the emergence of CSC-like properties in gastric cancer cells and, the underlying mechanism. Here, gastric cancer cells were co-cultured with a CagA-positive H. pylori strain or a CagA isogenic mutant strain. We found that H. pylori-infected gastric cancer cells exhibited CSC-like properties, including an increased expression of CSC specific surface markers CD44 and Lgr5, as well as that of Nanog, Oct4 and c-myc, which are known pluripotency genes, and an increased capacity for self-renewal, whereas these properties were not observed in the CagA isogenic mutant strain-infected cells. Further studies revealed that H. pylori activated Wnt/β-catenin signaling pathway in a CagA-dependent manner and that the activation of this pathway was dependent upon CagA-positive H. pylori-mediated phosphorylation of β-catenin at the C-terminal Ser675 and Ser552 residues in a c-met- and/or Akt-dependent manner. We further demonstrated that this activation was responsible for H. pylori-induced CSC-like properties. Moreover, we found the promoter activity of Nanog and Oct4 were upregulated, and β-catenin was observed to bind to these promoters during H. pylori infection, while a Wnt/β-catenin inhibitor suppressed promoter activity and binding. Taken together, these results suggest that H. pylori upregulates Nanog and Oct4 via Wnt/β-catenin signaling pathway to promote CSC-like properties in gastric cancer cells.

Keywords

Helicobacter pylori
Wnt/β-catenin
Nanog
Oct4
Gastric cancer

Abbreviations

H. pylori
Helicobacter pylori
CSC
cancer stem cell
cag PAI
cag pathogenicity island
CagA
cytotoxin-associated gene A
T4SS
type IV secretion system
TCF/LEF
T cell factor/lymphoid enhancer factor
Oct4
octamer-binding transcription factor 4
iPS
induced pluripotent stem
WT
wild-type
RTKs
receptor tyrosine kinases
EMT
epithelial-mesenchymal transition

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