Systematic Review and Meta-analysis:
DOI: 10.31557/apjcn.1701.20250205
Submitted: 2024-11-14
Published: 2025-02-05

Is Helicobacter pylori a Potential Risk Factor for Lung Cancer?

Department of Oncology, Tongren City People’s Hospital,Tongren City, Guizhou Province, China.
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Abstract

Helicobacter pylori (H. pylori) is a Gram-negative bacterium known primarily for its role in gastric diseases, including gastric cancer. However, emerging evidence links H. pylori infection to extragastric malignancies, particularly lung cancer. This review examines H. pylori’s biological characteristics, pathogenic mechanisms, and potential association with lung cancer development. It addresses H. pylori’s direct infection pathways, such as aspiration and microbiome transfer, and explores its impact on the immune system via inflammatory responses and molecular mimicry. Epidemiological data demonstrate inconsistent associations between H. pylori infection and lung cancer risk, though some studies suggest H. pylori-derived proteins, like CagA and VacA, might enhance carcinogenicity in lung tissues. Mechanistically, H. pylori-induced upregulation of inflammatory cytokines and cyclooxygenase-2 (COX-2) may contribute to lung carcinogenesis. Understanding these links could inform future therapeutic and preventive strategies for lung cancer in H. pylori-infected individuals. Further research is essential to clarify these associations and underlying mechanisms.

1.  Introduction

Helicobacter pylori (H.pylori) is a Gram-negative, spiral-shaped bacterium that infects the stomachs of up to half of the world’s population. The prevalence varies by country, ranging from 20% to 80% [1]. H. pylori has been classified by the World Health Organization as the primary causative factor of gastric cancer [2]. However, as research into its pathogenic mechanisms has deepened, H. pylori has also been linked to extragastric diseases, such as lung cancer [3]. Lung cancer is one of the leading causes of cancer-related deaths worldwide, accounting for approximately one-fifth of all cancer-related mortality [4]. Smoking is the most significant risk factor for lung cancer [5]. In China, the smoking rate among women is significantly lower than among men, yet the annual incidence rate among women can still reach 270,000 cases [6]. In fact, about 15-20% of male lung cancer patients and 50% of female lung cancer patients are non- smokers [7]. Second-hand smoke and exposure to cooking oil fumes are the primary causes [8-9]. An interesting phenomenon is that, despite global anti-smoking policies reducing the overall lung cancer incidence as expected, the incidence rate among non-smokers has been increasing [10]. This suggests the presence of non-smoking factors in lung cancer development, such as air pollution, viruses, bacterial infections, and lung cancer allergens [11]. Among bacterial factors, H. pylori stands out as a significant bacterium, with some studies suggesting a causal relationship between H. pylori and lung cancer [12], while other studies have found no such association [13]. This paper aims to provide a systematic review of the relationship between H. pylori and lung cancer.

2. Biological Characteristics and Pathogenic Mechanisms of H. pylori

2.1 Basic Characteristics of H. pylori

H.pylori is a Gram-negative, spiral-shaped bacterium that survives in the acidic environment of the stomach by breaking down urea through urease to neutralize gastric acid. The infection rate of H. pylori varies significantly worldwide, with the highest prevalence in Africa (70.1%) and the lowest in Oceania (24.4%) [14]. The pathogenicity of H. pylori depends on specific strains, genotypes, and the expression of virulence factors, which influence the interaction between the host environment and the bacterium [15].

2.2 Pathogenic Mechanisms

H.pylori affects the host through several virulence factors, including urease, cytotoxin-associated gene A (CagA), vacuolating cytotoxin A (VacA), and lipopolysaccharide (LPS). Table 1 presents H.pylori-related Independent Factors and Their Pathogenic Mechanisms.

Virulence Factors Mechanism Effects
Urease Production of HCO3- and H+ Neutralizing stomach acid and promoting bacterial colonization [16-17]Modulating host immune responses [18]Promoting cancer development [19]
Flagellum Motility Flagellar protein activation Enhancing bacterial motility [20-21]Facilitating colonization and protecting bacteria from escaping acidicenvironments [20, 22]
CagA T4SSTyrosine phosphorylation Facilitating the translocation of proteins and DNA into host cells [23] Enhancing cell vitality, reducing cell tight junctions, genomic instability, nucleotide damage [25-26]Promoting tumorigenesis [24]
VacA Vacuolation of epithelial cellsEndoplasmic reticulum (ER) stress Causes cell vacuolation [27] Leads to apoptosis [28] Autophagy activation [29] Promoting cell death [30]
LPS Activation of cytokines Src pathwayAltered dendritic cell (DC) antigen- presenting capacity Chronic systemic inflammation [34-36]Up-regulation of IL-1, IL-6, and TNF-α [35, 36]Inhibition of CD8 T cell antitumor response [39]
Table 1. H.pylori-related Independent Factors and Their Pathogenic Mechanisms.

Urease

H.pylori produces large amounts of urease, including intracellular urease and extracellular urease on the bacterial surface. Urease catalyzes the hydrolysis of urea to produce ammonia (NH3) and carbonic acid (H2CO3) [16], which further breaks down into bicarbonate (HCO3-) and H+, neutralizing gastric acid and creating a microenvironment conducive to H.pylori survival [17]. Additionally, urease modulates host immune responses through various mechanisms, such as altering opsonization, enhancing neutrophil and monocyte chemotaxis, promoting apoptosis via interaction with MHC class II receptors, or increasing pro-inflammatory cytokine release [18]. Urease also exhibits pro-angiogenic activity in gastric epithelial cells, activates platelets and neutrophils, and has pro-inflammatory properties independent of its enzymatic function, contributing to cancer development [19].

Flagella

Flagella are the locomotive organelles that allow bacteria to move within their environment. H.pylori has spiral-shaped flagella, typically 0.53 μm in diameter and approximately 3 μm long, with 2 to 6 sheathed flagella at one pole. Acid exposure activates flagellin proteins, which are recognized by TLR5 and drive NF-κB activation, enhancing motility [20-21]. The flagellar movement is powered by a proton motive force, which is generated by urease-driven hydrolysis [22].

Virulence Factors Associated with Pathogenicity

CagA

CagA is a key virulence factor of H.pylori, crucial to its pathogenicity. It is the only known protein secreted by the type IV secretion system (T4SS), a large translocon complex expressed on the surface of Gram-negative bacteria and archaea, which facilitates protein and DNA transfer into host cells in a contact-dependent manner [23]. Once inside the host cell, CagA is phosphorylated at the EPIYA motif (tyrosine residues) by Src family kinases. Phosphorylated CagA causes cytoskeletal rearrangements, leading to the formation of the “hummingbird phenotype,” which interferes with cell proliferation and polarity. Phosphorylated CagA also enhances cell survival, disrupts tight junctions, causes genomic instability, DNA damage, and activates the Wnt signaling pathway, increasing the risk of carcinogenesis [24-26].

VacA

VacA weakens the host cell barrier by inducing vacuole formation, disrupting tight junctions, and promoting apoptosis in gastric epithelial cells. Different VacA genotypes ( s1, s2, m1, m2) are closely associated with the severity of infection, and this diversity further influences its virulence [27]. Studies suggest that VacA induces apoptosis through the mitochondrial pathway by being internalized into gastric epithelial cells and targeting mitochondria via vacuole membrane ion channels or membrane disruption, leading to cell death [27-28]. Although the exact mechanism of VacA-induced mitochondrial apoptosis is unclear, some studies suggest that the VacA p33 subunit alone targets mitochondria to initiate apoptosis [29]. Other research indicates that VacA triggers endoplasmic reticulum stress, activating autophagy and increasing cell death in AGS cells [30].

Synergy Between CagA and VacA

CagA and VacA work synergistically to enhance pathogenicity. CagA induces DNA damage and genomic instability in host cells by activating inflammatory pathways, while VacA inhibits T cell proliferation, alters dendritic cell antigen presentation, and interferes with the immune system’s ability to recognize and eliminate infected cells. These mechanisms not only aggravate host cell damage but also facilitate persistent H. pylori infection, laying a potential foundation for carcinogenesis in distal organs, such as the lungs [31-33].

Lipopolysaccharide (LPS)

LPS is a major component of the H.pylori cell wall and triggers the upregulation of pro-inflammatory cytokines, including IL-1, IL-6, and TNF-α, leading to chronic systemic inflammation and immune stimulation [34-36]. Other studies suggest that H. pylori infection promotes a chronic inflammatory environment by activating the Src kinase (Src) signaling pathway[37-38] and upregulating the expression of pro-inflammatory IL-1, IL-6, and TNF-α [35, 36]. Notably, H.pylori inhibits CD8 T cell antitumor responses by altering dendritic cell (DC) antigen presentation [39].

3. Epidemiological Evidence of H. pylori and Lung Cancer

Risk H.pylori infection has been shown to significantly increase the risk of lung cancer [40, 41]. Behroozian et al. [42] studied 66 patients with histologically confirmed primary lung cancer and 66 controls, finding that the H.pylori seropositivity rate was 73% in the lung cancer group compared to 51% in the control group (95% CI: 1.14-5.54, OR: 2.51, P<0.01), suggesting that the H.pylori antibody seropositivity rate was significantly higher in lung cancer patients than in non-cancer patients. Ece et al. [43] conducted a study on 43 non-small cell lung cancer (NSCLC) patients and 28 controls, similarly demonstrating that the H.pylori seropositivity rate was significantly higher in lung cancer patients than in controls (93% vs. 42%, P<0.05). Additionally, they found that both VacA and CagA levels were higher in the lung cancer group, although only VacA reached statistical significance (81% vs. 42%, P<0.05). A prospective study by Yoon et al. [44] involving 295 newly diagnosed lung cancer patients and controls, examined 15 different H. pylori antibodies and found a positive association between H.pylori VacA (OR: 1.64; 95% CI: 1.02-2.62) and H.pylori Catalase (OR: 1.75; 95% CI: 1.11-2.77) with lung cancer risk. H.pylori-derived proteins have also been linked to smoking [45-46], and Yoon’s study [44] showed that in smokers, H.pylori VacA (OR: 2.53; 95% CI: 1.25-5.13) and H. pylori CagA (OR: 2.77; 95% CI: 1.35-5.70) were similarly associated with an increased lung cancer risk. These findings suggest a potential association between H.pylori infection and lung cancer development.

Pulmonary nodules are considered a precursor to lung cancer, and the risk of malignancy increases as the size of the nodule grows, particularly when the diameter exceeds 1 cm [47]. Mahasish et al. [48] compared the lung microbiomes of lung cancer patients, those with lung nodules, and smokers as controls, finding the highest H. pylori positivity rate in lung cancer patients. They identified HP1341 antibody as the most reactive among 233 H.pylori antibodies. The study further used specific antibody combinations to distinguish between lung adenocarcinoma patients and those with benign lung nodules or smokers, utilizing ROC curves (Receiver Operating Characteristic) to evaluate the discriminatory power of these antibody combinations (0.88 vs. 0.8). Sven et al. [49] in a retrospective study, found that patients who underwent H.pylori eradication therapy were negatively correlated with bronchial and lung cancers during subsequent follow-up (HR: 0.60; 95% CI: 0.44-0.83), while those who did not receive eradication therapy had a strong association with subsequent bronchial and lung cancers (HR: 1.51; 95% CI: 1.03-2.20).

However, study have shown no association between H.pylori and lung cancer [13]. But Paul et al. [39], in a retrospective analysis of two independent cohort studies, found that in both the French Dijon research center (60 NSCLC patients) and the Canadian Montreal research center (29 NSCLC patients), H.pylori was associated with reduced efficacy of immunotherapy (HR: 3.35, 95% CI: 1.69-6.66, P=0.001; HR: 2.39, 95% CI: 1.01-5.65, P=0.048). A case-control study by Koshiol et al. [50] compared 700 lung cancer patients (350 with lung adenocarcinoma and 350 with squamous cell carcinoma) and 700 controls. The results showed no significant difference in H.pylori positivity rates between the adenocarcinoma or squamous carcinoma groups and the control group (OR: 1.1, 95% CI: 0.75-1.6; OR: 1.1, 95% CI: 0.77-1.7). Similarly, no significant associations were observed with H.pylori CagA (OR: 1.1, 95% CI: 0.73-1.7) or H. pylori VacA (OR: 1.0, 95% CI: 0.65-1.6).

These inconsistencies may be attributed to differences in study design, sample size, geographic variation, and inadequate control of confounding variables. Overall, the relationship between H.pylori and lung cancer remains under investigation, and further large-scale or prospective studies are needed to draw more definitive conclusions. Table 2 presents the basic information of articles on the epidemiological relationship between Helicobacter pylori and lung cancer.

Author Sample Male Average age H.pylori test H.pylori rate(control, %l) OR CI P
Najafizadeh K(2007) [13] 80 57 NA H.pylori seroprevalence 52.5 1.35 0.56-3.25 0.65
Behroozian R(2010) [42] 132 103 NA H.pylori seroprevalence 73 2.51 1.14-5.54 < 0.05
Ece F (2005)[43] 71 35 NA H.pylori immunoblot NA NA NA < 0.01
Yoon HS(2022) [44] 590 306 57 H.pylori seroprevalence 56 1.29 0.85–1.95 > 0.05
Koshiol J(2012) [50] 1400 NA 58 H.pylori seroprevalence 78.8 1.1 0.75–1.6A0.77–1.7B > 0.05
Table 2. Basic Information of Articles on the Epidemiological Relationship between Helicobacter pylori and Lung Cancer.

NOTE:A represents adenocarcinoma, B represents squamous cell carcinoma

4. Possible Mechanisms of H. pylori-Induced Lung Cancer

4.1 Direct or Indirect Infection Mechanisms

It is currently theorized that H.pylori infection spreads directly through oral-oral or fecal-oral transmission within families [53]. The oral cavity, shared by both the respiratory and digestive systems, has been shown to harbor H.pylori [52]. Studies have detected H. pylori in the saliva of patients with laryngopharyngeal reflux [53] and in tracheal secretions [54]. Nur et al. [55] found H.pylori in lung cancer tissues using Giemsa staining, as well as in lung cancer specimens and bronchoalveolar lavage fluid, identifying H.pylori-derived proteins such as VacA. These proteins were shown to induce the production of IL-6 and IL-8 in human lung cells [3, 56]. This suggests that H.pylori may colonize lung tissue directly or cause disease indirectly through virulence factors like VacA. We hypothesize that H.pylori may colonize the lungs through the following pathways:

Aspiration

H.pylori can cause acid reflux, leading to reflux esophagitis [57]. H.pylori may enter the lower respiratory tract through vomiting, reflux, or aspiration, providing a physical pathway for colonization in the lungs.

Microbiome Transfer

The early colonization of gut and lung microbiota shows homology, as the microbiota enters the gut or lower respiratory tract via the oropharynx. The gut and lung engage in bidirectional regulation through microbial and immune interactions, amplifying immune signals in what is known as the gut-lung axis [58]. Dysbiosis in the gut microbiome could hypothetically enable the transfer of pathogens like H.pylori via this axis, affecting the lung microbiome and promoting H. pylori colonization.

4.2 Inflammatory and Immune Responses

Arismendi et al. [59] discovered that H.pylori induces lung damage by recruiting inflammatory cells and promoting the secretion of inflammatory cytokines. Lipopolysaccharide (LPS), a major component of H.pylori’s cell wall, can trigger the upregulation of pro- inflammatory cytokines such as IL-1, IL-6, and TNF-α, leading to chronic systemic inflammation and immune stimulation [34-36]. These cytokines may induce DNA double-strand breaks and genetic damage, leading to mutations that promote carcinogenesis [60]. H.pylori promotes the secretion of inflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8) and induces lung damage through its VacA exotoxin, thereby activating NF-κB signaling pathways [61].

4.3 Molecular Mimicry

Some studies suggest that the host immune response to bacteria can induce damage to both gastric and extra-gastric tissues through molecular mimicry [62]. This cross-reactivity may lead to the activation of self-reactive T or B cells, or direct damage from bacterial inhalation, which may contribute to chronic airway inflammation. Over time, this inflammation could lead to the malignant transformation of lung epithelial cells. Shan Xu et al. [63] reported six cases of drug-induced interstitial pneumonia following H.pylori eradication therapy, presenting with cough, shortness of breath, and fever. It is hypothesized that H. pylori may express antigens that mimic lung epithelial cell antigens, thereby activating antigen-specific immune responses through molecular mimicry, leading to chronic inflammation and eventual malignancy in the lung epithelium.

4.4 Host Response

Deng et al. [64] suggest that the interaction between H.pylori and the host primarily occurs at local adhesion points. H.pylori adhesin CagL, located at the tip of the Type IV secretion system (T4SS), can bind to β1 integrin receptors on epithelial cells, potentially activating focal adhesion kinase (FAK) and Src kinases. Activation (phosphorylation) of FAK and Src leads to the injection of CagA. Initially, CagA is phosphorylated by Src and subsequently interacts with tyrosine phosphatase (Shp-2) and C-terminal Src kinase (Csk), eventually deactivating FAK and Src. p130cas, a substrate of Src kinase, can be activated and recruited by Src, playing an oncogenic role in lung cancer cell invasion and migration.

4.5 Upregulation of Gastrin and Cyclooxygenase-2 (COX-2)

H. pylori infection induces the upregulation of COX-1, COX-2, and gastrin expression, which may further promote lung cancer by inducing bronchial epithelial cell proliferation [65]. There are also embryological explanations [66-68], suggesting that the lungs and digestive tract share the same origin from endodermal cells. When H.pylori infects the stomach, it can lead to an increased and prolonged release of gastrin into the circulation, which may stimulate the proliferation of lung cells.

5. Conclusion and Future Directions

Although increasing studies are exploring the relationship between H.pylori and lung cancer, current results are inconsistent. The main limitations are insufficient sample sizes, differences in study designs, and inadequate consideration of confounding factors. Future large-scale, multi-center prospective studies are needed to confirm this association. Future research should further investigate the molecular mechanisms linking H.pylori infection to lung cancer, as well as the specific impact of different H. pylori virulence factors on lung cancer development. If H.pylori infection is indeed associated with lung cancer, screening and eradication of H.pylori may become part of lung cancer prevention. Additionally, assessing H.pylori infection status may help inform personalized treatment strategies in lung cancer immunotherapy.

Acknowledgments

Statement of Transparency and Principals

• Author declares no conflict of interest

• Study was approved by Research Ethic Committee of author affiliated Institute.

• Study’s data is available upon a reasonable request.

• All authors have contributed to implementation of this research.

References

References

  1. Keikha M. Is there a relationship between Helicobacter pylori vacA i1 or i2 alleles and development into peptic ulcer and gastric cancer? A meta-analysis study on an Iranian population.. New Microbes New Infect. 2020; 36:100726.
  2. Shirani M, Pakzad R, Haddadi MH, Akrami S, Asadi A, Kazemian H, Moradi M, et al. The global prevalence of gastric cancer in Helicobacter pylori-infected individuals: a systematic review and meta-analysis. BMC infectious diseases. 2023; 23(1)DOI
  3. He J, Liu Y, Ouyang Q, Li R, Li J, Chen W, Hu W, et al. Helicobacter pylori and unignorable extragastric diseases: Mechanism and implications. Frontiers in Microbiology. 2022; 13DOI
  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: a cancer journal for clinicians. 2020; 70(1)DOI
  5. IARC, Tobacco Smoke and Involuntary Smoking. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 83, International Association for Research on Cancer, Lyon, 2004..
  6. Li C, Lei S, Ding L, Xu Y, Wu X, Wang H, Zhang Z, et al. Global burden and trends of lung cancer incidence and mortality. Chinese Medical Journal. 2023; 136(13)DOI
  7. Parkin DM, Bray F, Ferlay J., Pisani P. Global cancer statistics, 2002. CA: a cancer journal for clinicians. 2005; 55(2)DOI
  8. Taylor R, Najafi F, Dobson A. Meta-analysis of studies of passive smoking and lung cancer: effects of study type and continent. International Journal of Epidemiology. 2007; 36(5)DOI
  9. Yu ITS, Chiu Y, Au JSK, Wong T, Tang J. Dose-response relationship between cooking fumes exposures and lung cancer among Chinese nonsmoking women. Cancer Research. 2006; 66(9)DOI
  10. Dubin S, Griffin D. Lung Cancer in Non-Smokers. Missouri Medicine. 2020; 117(4)
  11. Wang D, Chan BC, Zhang B, Wong KC, Kan LL, Wong C. Dark under the Lamp: Neglected Biological Pollutants in the Environment Are Closely Linked to Lung Cancer. International Journal of Molecular Sciences. 2024; 25(6)DOI
  12. Zendehdel A, Roham M. Role of Helicobacter pylori infection in the manifestation of old age-related diseases. Molecular Genetics & Genomic Medicine. 2020; 8(4)DOI
  13. Najafizadeh K, Falah Tafti S, Shiehmorteza M, Saloor M, Jamali M. H pylori seroprevalence in patients with lung cancer. World Journal of Gastroenterology. 2007; 13(16)DOI
  14. Hooi JKY, Lai WY, Ng WK, Suen MMY, Underwood FE, Tanyingoh D, Malfertheiner P, et al. Global Prevalence of Helicobacter pylori Infection: Systematic Review and Meta-Analysis. Gastroenterology. 2017; 153(2)DOI
  15. Baj J, Forma A, Sitarz M, Portincasa P, Garruti G, Krasowska D, Maciejewski R. Helicobacter pylori Virulence Factors-Mechanisms of Bacterial Pathogenicity in the Gastric Microenvironment. Cells. 2020; 10(1)DOI
  16. Ansari S, Yamaoka Y. Helicobacter pylori Virulence Factors Exploiting Gastric Colonization and its Pathogenicity. Toxins. 2019; 11(11)DOI
  17. Athmann C., Zeng N., Kang T., Marcus E. A., Scott D. R., Rektorschek M., Buhmann A., Melchers K., Sachs G.. Local pH elevation mediated by the intrabacterial urease of Helicobacter pylori cocultured with gastric cells. The Journal of Clinical Investigation. 2000; 106(3)DOI
  18. Schmalstig AA, Benoit SL, Misra SK, Sharp JS, Maier RJ. Noncatalytic Antioxidant Role for Helicobacter pylori Urease. Journal of Bacteriology. 2018; 200(17)DOI
  19. Olivera-Severo D, Uberti AF, Marques MS, Pinto MT, Gomez-Lazaro M, Figueiredo C, Leite M, Carlini CR. A New Role for Helicobacter pylori Urease: Contributions to Angiogenesis. Frontiers in Microbiology. 2017; 8DOI
  20. Merrell DS, Goodrich ML, Otto G, Tompkins LS, Falkow S. pH-regulated gene expression of the gastric pathogen Helicobacter pylori. Infection and Immunity. 2003; 71(6)DOI
  21. Zou J, Zhao X, Shi Z, Zhang Z, Vijay-Kumar M, Chassaing B, Gewirtz AT. Critical Role of Innate Immunity to Flagellin in the Absence of Adaptive Immunity. The Journal of Infectious Diseases. 2021; 223(8)DOI
  22. Yoshiyama H., Nakazawa T.. Unique mechanism of Helicobacter pylori for colonizing the gastric mucus. Microbes and Infection. 2000; 2(1)DOI
  23. Cover TL, Lacy DB, Ohi MD. The Helicobacter pylori Cag Type IV Secretion System. Trends in Microbiology. 2020; 28(8)DOI
  24. Nagase L, Hayashi T, Senda T, Hatakeyama M. Dramatic increase in SHP2 binding activity of Helicobacter pylori Western CagA by EPIYA-C duplication: its implications in gastric carcinogenesis. Scientific Reports. 2015; 5DOI
  25. Ding S, Goldberg JB, Hatakeyama M. Helicobacter pylori infection, oncogenic pathways and epigenetic mechanisms in gastric carcinogenesis. Future Oncology (London, England). 2010; 6(5)DOI
  26. Segal E. D., Cha J., Lo J., Falkow S., Tompkins L. S.. Altered states: involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proceedings of the National Academy of Sciences of the United States of America. 1999; 96(25)DOI
  27. Palframan SL, Kwok T, Gabriel K. Vacuolating cytotoxin A (VacA), a key toxin for Helicobacter pylori pathogenesis. Frontiers in Cellular and Infection Microbiology. 2012; 2DOI
  28. Luo J, Li C, Liu S, Yu W, Tang S, Cai H, Zhang Y. Overexpression of Helicobacter pylori VacA N-terminal fragment induces proinflammatory cytokine expression and apoptosis in human monocytic cell line through activation of NF-κB. Canadian Journal of Microbiology. 2013; 59(8)DOI
  29. Domańska G, Motz C, Meinecke M, Harsman A, Papatheodorou P, Reljic B, Dian-Lothrop EA, et al. Helicobacter pylori VacA toxin/subunit p34: targeting of an anion channel to the inner mitochondrial membrane. PLoS pathogens. 2010; 6(4)DOI
  30. Zhu P, Xue J, Zhang Z, Jia Y, Tong Y, Han D, Li Q, Xiang Y, Mao X, Tang B. Helicobacter pylori VacA induces autophagic cell death in gastric epithelial cells via the endoplasmic reticulum stress pathway. Cell Death & Disease. 2017; 8(12)DOI
  31. Salvatori S, Marafini I, Laudisi F, Monteleone G, Stolfi C. Helicobacter pylori and Gastric Cancer: Pathogenetic Mechanisms. International Journal of Molecular Sciences. 2023; 24(3)DOI
  32. Shimizu T, Chiba T, Marusawa H. Helicobacter pylori-Mediated Genetic Instability and Gastric Carcinogenesis. Current Topics in Microbiology and Immunology. 2017; 400DOI
  33. Qumar S, Nguyen TH, Nahar S, Sarker N, Baker S, Bulach D, Ahmed N, Rahman M. A comparative whole genome analysis of Helicobacter pylori from a human dense South Asian setting. Helicobacter. 2021; 26(1)DOI
  34. Kanbay M, Kanbay A, Boyacioglu S. Helicobacter pylori infection as a possible risk factor for respiratory system disease: a review of the literature. Respiratory Medicine. 2007; 101(2)DOI
  35. Arnold IC, Dehzad N, Reuter S, Martin H, Becher B, Taube C, Müller A. Helicobacter pylori infection prevents allergic asthma in mouse models through the induction of regulatory T cells. The Journal of Clinical Investigation. 2011; 121(8)DOI
  36. Jackson L, Britton J, Lewis SA, McKeever TM, Atherton J, Fullerton D, Fogarty AW. A population-based epidemiologic study of Helicobacter pylori infection and its association with systemic inflammation. Helicobacter. 2009; 14(5)DOI
  37. Wei L, Yang Y, Zhang X, Yu Q. Anchorage-independent phosphorylation of p130(Cas) protects lung adenocarcinoma cells from anoikis. Journal of Cellular Biochemistry. 2002; 87(4)DOI
  38. Huang W, Deng B, Wang R, Tan Q, He Y, Jiang Y, Zhou J. BCAR1 protein plays important roles in carcinogenesis and predicts poor prognosis in non-small-cell lung cancer. PloS One. 2012; 7(4)DOI
  39. Oster P, Vaillant L, Riva E, McMillan B, Begka C, Truntzer C, Richard C, et al. Helicobacter pylori infection has a detrimental impact on the efficacy of cancer immunotherapies. Gut. 2022; 71(3)DOI
  40. Zhuo W, Zhu B, Xiang Z, Zhuo X, Cai L, Chen Z. Assessment of the relationship between Helicobacter pylori and lung cancer: a meta-analysis. Archives of Medical Research. 2009; 40(5)DOI
  41. Mounika P. Helicobacter pylori Infection and Risk of Lung Cancer: A Meta-Analysis. Lung Cancer International. 2013; 2013DOI
  42. Behroozian R, Moradkhan E. The assessment of probable relationship between lung cancer and Helicobacter pylori infection. Tropical Gastroenterology: Official Journal of the Digestive Diseases Foundation. 2010; 31(1)DOI
  43. Ece F, F Hatabay N, Erdal N, Gedik C, Guney C, Aksoy F. Does Helicobacter pylori infection play a role in lung cancer?. Respiratory Medicine. 2005; 99(10)DOI
  44. Yoon H, Shu X, Cai H, Zheng W, Wu J, Wen W, Courtney R, et al. Associations of lung cancer risk with biomarkers of Helicobacter pylori infection. Carcinogenesis. 2022; 43(6)DOI
  45. Peleteiro B, Lunet N, Figueiredo C, Carneiro F, David L, Barros H. Smoking, Helicobacter pylori virulence, and type of intestinal metaplasia in Portuguese males. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2007; 16(2)DOI
  46. Wang X, Yan H, Terry PD, Wang J, Cheng L, Wu W, Hu S. Interactions between CagA and smoking in gastric cancer. World Journal of Gastroenterology. 2011; 17(28)DOI
  47. Schmid-Bindert G, Vogel-Claussen J, Gütz S, Fink J, Hoffmann H, Eichhorn ME, Herth FJF. Incidental Pulmonary Nodules - What Do We Know in 2022. Respiration; International Review of Thoracic Diseases. 2022; 101(11)DOI
  48. Shome M, Gao W, Engelbrektson A, Song L, Williams S, Murugan V, Park JG, Chung Y, LaBaer J, Qiu J. Comparative Microbiomics Analysis of Antimicrobial Antibody Response between Patients with Lung Cancer and Control Subjects with Benign Pulmonary Nodules. Cancer Epidemiology, Biomarkers & Prevention: A Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2023; 32(4)DOI
  49. Loosen SH, Mertens A, Klein I, Leyh C, Krieg S, Kandler J, Luedde T, Roderburg C, Kostev K. Association between Helicobacter pylori and its eradication and the development of cancer. BMJ open gastroenterology. 2024; 11(1)DOI
  50. Koshiol J, Flores R, Lam TK, Taylor PR, Weinstein SJ, Virtamo J, Albanes D, et al. Helicobacter pylori seropositivity and risk of lung cancer. PloS One. 2012; 7(2)DOI
  51. Dunn B. E., Cohen H., Blaser M. J.. Helicobacter pylori. Clinical Microbiology Reviews. 1997; 10(4)DOI
  52. Ogaya Y, Kadota T, Hamada M, Nomura R, Nakano K. Characterization of the unique oral microbiome of children harboring Helicobacter pylori in the oral cavity. Journal of Oral Microbiology. 2024; 16(1)DOI
  53. Asyari A, Yerizel E, Eka Putra A, et al. Analysis of Helicobacter pyloriinSaliva of Patients with Laryngopharyngeal Reflux and Non-Laryngopharyngeal Reflux. Open Access Macedonian Journal of Medical Sciences. 2022; 10(B):2433-2436.
  54. Mitz H. S., Farber S. S.. Demonstration of Helicobacter pylori in tracheal secretions. The Journal of the American Osteopathic Association. 1993; 93(1)DOI
  55. Buyukpinarbasili N. Helicobacter pylori as an Etiologic Factor in Primary Lung Carcinoma. Bezmialem Science. 2018; 6(2):134-137. DOI
  56. Nakashima S, Kakugawa T, Yura H, Tomonaga M, Harada T, Hara A, Hara S, et al. Identification of Helicobacter pylori VacA in human lung and its effects on lung cells. Biochemical and Biophysical Research Communications. 2015; 460(3)DOI
  57. Gao B, Duan L, Wang K, Xia Z, Lin S. The roles of Helicobacter pylori and pattern of gastritis in the pathogenesis of reflux esophagitis. Zhonghua Yi Xue Za Zhi. 2006; 86(38)
  58. Zuo ZT, Ma Y, Sun Y, Bai CQ, Ling CH, Yuan FL. The Protective Effects of Helicobacter pylori Infection on Allergic Asthma. International Archives of Allergy and Immunology. 2021; 182(1)DOI
  59. Arismendi Sosa A. C., Salinas Ibáñez A. G., Pérez Chaca M. V., Penissi A. B., Gómez N. N., Vega A. E.. Study of Helicobacter pylori infection on lung using an animal model. Microbial Pathogenesis. 2018; 123DOI
  60. Lim NR, Chung WC. Helicobacter pylori-associated Chronic Atrophic Gastritis and Progression of Gastric Carcinogenesis. The Korean Journal of Gastroenterology = Taehan Sohwagi Hakhoe Chi. 2023; 82(4)DOI
  61. Chen M, Huang X, Gao M, Yang Z, Fang Z, Wei J, Wu B. Helicobacter pylori promotes inflammatory factor secretion and lung injury through VacA exotoxin-mediated activation of NF-κB signaling. Bioengineered. 2022; 13(5)DOI
  62. Durazzo M, Adriani A, Fagoonee S, Saracco GM, Pellicano R. Helicobacter pylori and Respiratory Diseases: 2021 Update. Microorganisms. 2021; 9(10)DOI
  63. Xu S, Wu X, Chen E, Ying K. Anti-Helicobacter pylori Infection Treatment and Pulmonary Hypersensitivity: Case Series and Review of the Literature. The Clinical Respiratory Journal. 2024; 18(8)DOI
  64. Deng B, Li Y, Zhang Y, Bai L, Yang P. Helicobacter pylori infection and lung cancer: a review of an emerging hypothesis. Carcinogenesis. 2013; 34(6)DOI
  65. Gocyk W., Nikliński T., Olechnowicz H., Duda A., Bielański W., Konturek P. C., Konturek S. J.. Helicobacter pylori, gastrin and cyclooxygenase-2 in lung cancer. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2000; 6(6)
  66. Smith J. T., Pounder R. E., Nwokolo C. U., Lanzon-Miller S., Evans D. G., Graham D. Y., Evans D. J.. Inappropriate hypergastrinaemia in asymptomatic healthy subjects infected with Helicobacter pylori. Gut. 1990; 31(5)DOI
  67. Kai H., Ito M., Kitadai Y., Tanaka S., Haruma K., Chayama K.. Chronic gastritis with expression of inducible nitric oxide synthase is associated with high expression of interleukin-6 and hypergastrinaemia. Alimentary Pharmacology & Therapeutics. 2004; 19(12)DOI
  68. De Francesco V., Zullo A., Rinaldi V., Hassan C., Ballanti P., Winn S., Diana F., Morini S., Attili A. F.. Relationship between antral lymphocyte density and basal gastrin levels in patients with Helicobacter pylori infection. Digestive and Liver Disease: Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2000; 32(8)DOI