Update on molecular pathogenesis of Helicobacter pylori-induced gastric cancer

Table 1 Key virulence factors involved in Helicobacter pylori infection

Key virulence factors	Mechanisms of action
CagPAI and CagA	CagPAI encodes the type IV secretion system and effector protein CagA. CagA is translocated into epithelial cells, where it phosphorylates and triggers signaling cascades associated with gastric cancer pathogenesis
VacA	VacA is a secreted toxin that induces vacuolation in host cells. It affects T cell proliferation, mitochondrial function, apoptosis, IL-8 release, and autophagy. Genetic polymorphisms in VacA influence its activity and are associated with the risk of gastric cancer
Urease	Urease hydrolyzes urea to neutralize stomach acid and maintain an optimal pH for bacterial survival
Flagella	Flagella facilitate bacterial movement and colonization. They also contribute to biofilm formation and modulate the immune response by inducing the release of IL-8
Outer membrane proteins (OMPs)	OMPs like BabA, SabA, and OipA interact with host receptors, promoting long-term colonization, chronic inflammation, and IL-8 secretion

CagA: Cytotoxin-associated gene A; BabA: Blood group antigen-binding adhesion A; SabA: Sialic acid-binding adhesion A; VacA: Vacuolating cytotoxin gene A; IL: Interleukin.

Table 2 Some other virulence factors involved in the pathogenicity of Helicobacter pylori infection

Virulence factors	Mechanisms of action
Lipopolysaccharide	Triggers several signaling pathways
	Induces several inflammatory responses
	Induces immune responses
	Disrupts the mucus secretion
	Shielding the organism against toxic materials
Phospholipase	Activates signaling pathways (e.g., ERK1/2)
	Trigger chronic inflammation
	Enhances bacterial colonization and survival
	Involved in the degradation of lipids and damage to the mucus layer
Heat shock proteins	Enhance adherence to epithelial surfaces
	Involved in urease activation
	Control apoptosis and autophagy
	Help to maintain the structure and properties of the effector proteins
	Protect the cell from reactive oxygen species (ROS)
	Induce the production and release of IL-8, TNF-α and COX-2
Arginase	Prevents bacterial killing
	Prevents T-cell proliferation
	Impair immune responses
	Stimulate apoptosis
	Help the H. pylori to withstand the acidic environment
Superoxide dismutase	Protects the cell from ROS
	Enhances colonization
	Inhibits the production of cytokines
	Stimulates macrophage activation
γ-glutamyl-transferase	Facilitates apoptosis and necrosis
	Induces the release of pro-inflammatory proteins
	Induces the release of ROS
	Stimulates DNA damage
Cholesteryl α-glucosyltransferase (αCgT)	Shields H. pylori from immunological attack
	Stimulates the production of pro-inflammatory proteins (e.g., IL-8)
	Enhances bacterial growth and its resistance to antibiotics

TNF-α: Tumor necrosis factor alpha; IL: Interleukin; Helicobacter pylori: H. pylori.

Table 3 Signaling pathways activated by Helicobacter pylori infection that promote uncontrolled cell proliferation

Signaling pathways	Molecular mechanisms involved in gastric cancer induced by H. pylori
STAT3 pathway	H. pylori activates the STAT3 pathway through upregulation of IL-6, CagA-mediated SHP-2 activation, and TLR2 interaction. STAT3 regulates downstream target genes involved in cellular processes such as development, proliferation, differentiation, EMT, invasion, and metastasis
NF-κB pathway	H. pylori activates NF-κB through direct activation by CagA, IKK kinase, and upregulation of pro-inflammatory factors. NF-κB transcriptionally regulates genes involved in cell cycle progression, apoptosis inhibition, and cross-regulates with other tumor signaling pathways
Wnt/β-catenin	H. pylori activates the Wnt/β-catenin pathway through CagA-mediated accumulation and nuclear translocation of β-catenin. Activation of this pathway disrupts cell cycle regulation, inhibits apoptosis, induces EMT, and promotes tumor cell proliferation, motility, and invasion. Cross-regulation between Wnt/β-catenin and other pathways enhances oncogenic effects
Miscellaneous signaling pathways	H. pylori activates additional signaling pathways including the MAPK pathway (ERK, JNK, p38), PI3K/Akt pathway, Hippo pathway, and various other pathways (HGF/Met, TGF-β, Hedgehog, Notch). These pathways are involved in regulating proliferation, survival, migration, invasion, differentiation, apoptosis, stem cell properties, microRNA map, and exhibit complex cross-regulatory interactions with each other and with the classical pathways

Helicobacter pylori: H. pylori.