- Helicobacter pylori is a gastric pathogen closely associated with the development of gastric cancer. One of its major virulence factors, the cytotoxin-associated gene A (CagA) protein, is delivered into host gastric epithelial cells via the type IV secretion system.
- Once inside the host cell, CagA becomes tyrosine-phosphorylated and interacts with various signaling molecules, leading to morphological and functional changes in the host.
- In AGS gastric epithelial cells, CagA expression induces a characteristic elongation of the cells known as the “hummingbird phenotype,” a response that resembles certain features of epithelial-to-mesenchymal transition (EMT).
- EMT is a biological process in which epithelial cells lose their polarity and cell-cell adhesion properties, gaining migratory and invasive characteristics typical of mesenchymal cells. It plays essential roles in embryonic development, tissue repair, and cancer progression.
- The hummingbird phenotype induced by CagA shows morphological similarities to EMT, including cell elongation, loss of junctional integrity, and increased motility. Although AGS cells are already deficient in E-cadherin, a key epithelial marker, CagA further disrupts cell-cell junctions by targeting proteins like ZO-1, JAM-A, and β-catenin, thereby weakening epithelial characteristics.
- On a molecular level, CagA activates signaling pathways that are commonly involved in EMT regulation. These include the ERK/MAPK and PI3K/Akt pathways, as well as Wnt/β-catenin and YAP/TAZ signaling. Activation of these pathways leads to cytoskeletal rearrangements, increased cell scattering, and in some cases, the expression of mesenchymal markers such as vimentin and transcription factors like ZEB1 and Snail. These markers are known regulators of EMT and are associated with increased cellular invasiveness. However, the expression of mesenchymal markers in CagA-expressing AGS cells is variable and often context-dependent, indicating that the induced phenotype is partial and does not represent a full EMT.
- Another key difference between classical EMT and the phenotype induced by CagA is reversibility. While EMT can result in stable mesenchymal traits, particularly in cancer progression, the changes seen in AGS cells due to CagA are often transient and dependent on continuous presence of the bacterial protein. Thus, the transformation is better described as an EMT mimic—a partial reprogramming of the epithelial state without full transition to a mesenchymal identity.
- In summary, CagA induces EMT-like changes in AGS cells through both morphological remodeling and activation of EMT-associated signaling pathways. Although it does not trigger a complete EMT, the resulting phenotype mimics several core features of the process, including increased motility, cytoskeletal changes, and junctional disruption. These findings highlight how bacterial pathogens like H. pylori can exploit host signaling machinery to drive cell plasticity, potentially contributing to disease progression and oncogenesis.
