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

• Published in: Journal of cellular biochemistry Vol. 125; no. 3; pp. e30527 - n/a
• Main Authors: Chen, Zheng‐wei, Dong, Zhe‐bin, Xiang, Han‐ting, Chen, Sang‐sang, Yu, Wei‐ming, Liang, Chao
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2024
• Subjects: 1-Phosphatidylinositol 3-kinase; Adenocarcinoma; AKT protein; Antigens, Bacterial - metabolism; Bacterial Proteins - metabolism; CagA; CagA protein; Cancer; cancer stem cells; CD44 antigen; Cytoplasm; Cytotoxins - metabolism; FOXO3 protein; FOXO3a; Gastric cancer; Gastric Mucosa - metabolism; Helicobacter Infections - pathology; Helicobacter pylori; Humans; Metastases; Neoplastic Stem Cells - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Signal transduction; Spheroids; Stem cells; Stomach Neoplasms - metabolism; Surface markers; Tumor cells; Tumors; Virulence; FOXO3a; cancer stem cells; Helicobacter pylori; gastric cancer; CagA
• ISSN: 0730-2312; 1097-4644; 1097-4644
• DOI: 10.1002/jcb.30527

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.