Helicobacter pylori CagA protein induces gastric cancer stem cell‐like properties through the Akt/FOXO3a axis

Abstract

The presence of Helicobacter pylori (H. pylori) infection poses a substantial risk for the development of gastric adenocarcinoma. The primary mechanism through which H. pylori exerts its bacterial virulence is the cytotoxin CagA. This cytotoxin has the potential to induce inter‐epithelial mesenchymal transition, proliferation, metastasis, and the acquisition of stem cell‐like properties in gastric cancer (GC) cells infected with CagA‐positive H. pylori. Cancer stem cells (CSCs) represent a distinct population of cells capable of self‐renewal and generating heterogeneous tumor cells. Despite evidence showing that CagA can induce CSCs‐like characteristics in GC cells, the precise mechanism through which CagA triggers the development of GC stem cells (GCSCs) remains uncertain. This study reveals that CagA‐positive GC cells infected with H. pylori exhibit CSCs‐like properties, such as heightened expression of CD44, a specific surface marker for CSCs, and increased ability to form tumor spheroids. Furthermore, we have observed that H. pylori activates the PI3K/Akt signaling pathway in a CagA‐dependent manner, and our findings suggest that this activation is associated with the CSCs‐like characteristics induced by H. pylori. The cytotoxin CagA, which is released during H. pylori infection, triggers the activation of the PI3K/Akt signaling pathway in a CagA‐dependent manner. Additionally, CagA inhibits the transcription of FOXO3a and relocates it from the nucleus to the cytoplasm by activating the PI3K/Akt pathway. Furthermore, the regulatory function of the Akt/FOXO3a axis in the transformation of GC cells into a stemness state was successfully demonstrated.

Prognosis and Treatment of Gastric Cancer: A 2024 Update

“…From the point of view of experimental approaches, H. pylori-infected cytotoxinassociated gene A (CagA)-positive GC cells exhibit the characteristics of cancer stem cells, including enhanced expression of cluster of differentiation (CD) 44, which is a particular surface marker for cancer stem cells. In addition, they present a greater capacity to form tumor spheroids than other GC cell lines [8].…”

Helicobacter pylori Infection in Patients with Gastric Cancer: A 2024 Update

“…GC cells' transition into a stemness stage and the regulating role of the Akt/FOXO3a axis. [23] For therapeutic intervention, CircPGD might be a promising new target. [24] One potential new target for GC therapy is lnc-PLCB1.…”

“…CagA is the main method by which H. pylori exhibits bacterial pathogenicity. Through phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway activation, CagA suppresses forkhead box O3 (FOXO3a) transcription and translocates it from the nucleus to the cytoplasm [ 23 ].…”