Effects and mechanisms of Helicobacter pylori infection on the occurrence of extra-gastric tumors

Table 1 The mechanisms of Helicobacter pylori infection on the occurrence of extra-gastric tumors

Cancers affected by H. pylori	Roles of H. pylori	Effects and mechanisms of H. pylori infection	Results
CRC	Damaging mucosal barrier	Decreased expression of junctional molecules and the glycosylation of MUC1 in gastrointestinal epithelium[48]	Affecting the assembly and function of the adherent junctions and breaking the mucosal barrier that protects the epithelial cells from the degradative enzymes
		Inducing goblet cells switch to less differentiated ones and a lower expression of Atoh[49]	A loss of goblet cells
	Damaging immune barrier	Inducing loss of Treg cells and their differentiation into Foxp3+ IL-17A+ T cells[47]	Inducing a pro-inflammatory immune response
		Enhanced indoleamine 2,3-dioxygenase activity and increased ratio of the kynurenine to tryptophan low serum nitrite levels[51]	Enhancing systemic immune tolerance
	Damaging microbial barrier	Increasing Akkermansia spp and Ruminococcus spp[47]	Altering the microbiota of the lower gastrointestinal tract, favoring mucus-degrading microbiota and inducing a pro-inflammatory and pro-carcinogenic microbiota signature
		Elevating relative abundance of temperate phages[55]	Expanding virulence by phage-mediated horizontal gene transfer and contributing to the development of CRC
	Inducing hypergastrinemia	Promoting the secretion of gastrin and COX-2 expression[39]	Contribute to the initiation and promotion of CRC
	Acting synergistically with metabolic disease	Combination with elevated HbA1c or diabetes mellitus[63,64]	Increasing the risk of colorectal adenoma
Lung cancer	Promoting lung cancer	Gastroesophageal reflux of H. pylori urease may trigger for the initiation of pulmonary granuloma[71]	Inducing the risk of lung damage and inflammation
		Promoting inflammatory factor secretion and inducing lung injury through the activation of NF-κB signaling via VacA exotoxin[72]
		Acting synergically with the effects of smoking or air-pollution to establish and perpetuate an inflammatory reaction[74]
		Inducing dysregulation of the gut microbiome[77]	May increase susceptibility to lung cancer
	No clear evidence of a causal association between H. pylori infection and respiratory diseases	A limited number of underpowered studies reporting contrasting results[78]	The correlation between H. pylori and lung cancer as well as its underlying mechanisms, remains to be elucidated with precision
CCA and GBC	Associating with the carcinogenesis of CCA	Enhancing inflammation, promoting proliferation of biliary cells, inducing inflammation-mediated DNA damage[79]	Contributing to the development of CCA
	Involving in GBC development	Damaging human gallbladder epithelial cells[81]	Contributing to the development of GBC
		Acting as a gallstone disease lithogenic factor[82]
		inducing more aggressive inflammation in in gallbladder mucosa with other bacteria[79,83]
HCC	The relationship between H. pylori infection and risk of HCC is still controversial	Inducing epithelial cell inflammation, proliferation and disturbance of apoptosis and DNA synthesis[86]	Leading to HCC development
		Coinfection with HBV or HCV[86]
		No associations between H. pylori and liver diseases[96-98]	No correlations with HCC or playing an anti-HCC role
		Hpn, a nickel-affinity protein from H. pylori can suppress cell growth and induce apoptosis of HCC[99]
Esophageal cancer	The relationship between H. pylori infection and risk of Esophageal cancer is still controversial	Gastrin maintains chronic inflammation and certain pathophysiology molecular alterations[108,109]	May contribute to esophageal cancer development
		Increased IL-8 via p38 MAPK pathway and the declined expression of SHP-2 mRNA to induce cell proliferation[110], LPS-TLR4 signaling associating with the activation of ERK and p38 MAPK pathways[110]
		Heterogeneity and improper handling of potential confounding factors[101-103]	Arguing that whether H. pylori is a protective agent or a cause of esophageal cancer
PCa	The relationship between H. pylori infection and risk of prostate cancer is still controversial	Affecting human microbiome[112]	May contribute to the development of prostate cancer
		CagA gene integrations in PPP1R9A and NCAM1 genes[113]
		Associating with a reduced risk of mortality in PCa patients receiving androgen deprivation therapy[113]	Negative correlations with prostate cancer
Urinary bladder carcinoma	Associating with the development of urinary bladder carcinoma	Inducing inflammation in the urinary bladder and pelvis[116], associating with the development of mucosa-associated lymphoid tissue lymphoma of the urinary bladder[116]	May contribute to urinary bladder carcinoma but lacking of direct evidence and further studies are needed to confirm

H. pylori: Helicobacter pylori; PCa: Prostate cancer; CRC: Colorectal cancer; Treg: Regulatory T cell; HbA1c: Hemoglobin A1c; NF-κB: Nuclear factor-kappa B; VacA: Vacuolating cytotoxin A; CCA: Cholangiocarcinoma; GBC: Gallbladder carcinoma; HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus; HCV: Hepatitis C virus; CagA: Cytotoxin-associated gene A; Hpn: Histidine-rich protein.