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Helicobacter pylori Virulence Factors, Pathogenicity, and Gastric Cancer 123
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readers are referred to the following references (Chatre et al. 2017 ; Necchi et al.
2017; Eslami et al. 2019; Chauhan et al. 2019 ; Chen et al. 2022 ).
VacA reaches mitochondria and proceeds to release cytochrome C from the
mitochondria, loss of adenosine triphosphate (ATP) formation, and activating Bax
and Bak proapoptotic proteins, inducing apoptosis via a mitochondrial dependent
pathway. Also, VacA forms pores in the mitochondrial membrane that disrupts the
electrochemical membrane potential (Foo et al. 2010; Galmiche and Rassow 2010).
VacA influences β-catenin via the activation of phosphatidylinositol 3-kinase/Akt,
PI3K/Akt signaling pathway, thus contributing to the oncogenic potential of
H. pylori. The glycogen synthase kinase 3β (GSK-3β) regulates cell proliferation
and survival, which is inhibited by Akt phosphorylation. In addition, the GSK-3β
phosphorylates β-catenin, resulting in β-catenin ubiquitination and its proteasomal
degradation. Nakayama et al. showed that VacA phosphorylates Akt; as a result,
GSK-3β is phosphorylated and inactivated. This phosphorylation frees the β-catenin,
such that β-catenin accumulates in the cytoplasm and then subsequently translocates
to the nucleus (Nakayama et al. 2009). In the nucleus, β-catenin binds to T cell
factor/lymphoid enhancer factor (TCF/LEF) to induce the transcription of β-catenindependent genes such as cyclin D1 and cdx1, which are implicated in gastric cancer
(Necchi et al. 2017 ; Alipour 2021).
• VacA Structure and Allelic Variation
The vacA gene encodes a 140 kDa protoxin. This protoxin is composed of a
signal sequence, a passenger domain, and an auto-transporter β-barrel. The
signal sequence allows the passage of the protoxin through the inner bacterial
membrane. The passenger domain is cleaved to form a mature monomer toxin of
88 kDa. The mature toxin consists of two fragments, a p33 and p55. The p33 is a
33 kDa N-terminal fragment (1–311 amino acids) and the p55 is a 55 kDa C-terminal
fragment (from 312–821 amino acids) (Raghunathan et al. 2018). The autotransporter domain functions as a type V secretion system and allows the translocation of the toxin across the outer bacterial membrane.
Both vacuolation and membrane polarization are p33/p55 subunit dependent. A
portion of the p33 is responsible for pore formation. The p33 domain is necessary for
VacA insertion into membranes, while there is no potential contribution from either
the oligomerization or the presence of transmembrane repeats in the p33 on VacA
insertion into membrane (Pyburn et al. 2016). The full-length p33 domai n and
111 amino acids from the N-terminal portion of the p55 domain are required for
cell vacuolation. The p55 domain alone is sufficient for VacA to bind to lipid rafts.
Furthermore, the deletion of the unique amino-terminal hydrophobic region of VacA
(32 amino acids) is associated with the loss of vacuolating activity and a defect in the
activity of channel formation. Addi tionally, the mutations at glycine resi dues (G14
and G18) in the three tandem GXXXG motifs included within the hydrophobic
region resulted in lacking VacA activity in channel formation and vacuolation
(McClain et al. 2003).
124 A. M. Elgohary et al.
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Although all H. pylori strains are VacA positive, their virulence and toxicity are
based on the allelic variations in the vacA gene. Polymorphism in the vacA gene
sequence has been detected in five distinct regions: the s-region with s1 and s2
variants, m-region (m1 and m2 alleles), i-region (i1-i2 and i3 alleles), d-region
(d1 and d2), and c-region (exclusion c1 and inclusion c2) (Trang et al. 2016).
The s-region is located within the signal sequence region and the N-terminal of
the p33 subunit. The i-region is located close to the c-terminal of the p33 subunit.
The m-region is located within the p55 subuni t. The d-region lies at the junction
between p33 and p55 subunits. Multiple reports are concerned with the combination
of different alleles in disease progression and severity and the context of strains from
distinct geographical areas (Mottaghi et al. 2016; Inagaki et al. 2017; AtriscoMorales et al. 2018). In essence, the studies pointed to the s1, m1, i1, d1, and c1
combined alleles are associated with the increased risk of gastric cancer (Bakhti et al.
2016; McClain et al. 2017; El Khadir et al. 2020).
1.3.2 Cytotoxin-Associated Gene A (CagA)
CagA is a 120–145 kDa oncoprotein encoded on the ~40 kb cag pathogenicity island
(Cag-PAI). It is delivered into the gastric epithelial cells by the type IV secretion
system T4SS (Akopyants et al. 1998). The highly virulent H. pylori strain is CagA
positive strain. Many T4SS proteins interact with α5β1 integrin, allowing CagA into
the cytoplasm across the cell membrane (Censini et al. 1996; Jiménez-Soto et al.
2009). CagA protein is phosphorylated in the cytoplasm by Src protein kinase at
EPIYA (Glu-Pro-Ile-Tyr-Ala) motif, which is more repeated in the carboxylic
terminal. This motif is classified into four (EPIYA-A, EPIYA-B, EPIYA-C, and
EPIYA-D) based on the sequence and number of repeats flanking the motif. Geographically, CagA is subdivided into Western and East Asian, which are
characterized by the presence of EPIYA-C and EPIYA-D, respectively. Among all
H. pylori strains, CagA N-terminal is characterized to be highly conservative while
its C-terminal region is characteri zed to have an intrinsically disordered behavior
(Rojas-Rengifo et al. 2018; Cover et al. 2020).
Like the EPIYA motif, the CagA multimerization (CM) motif, another polymorphism within CagA is a 16 amino acid sequence within the EPIYA repeat region.
Meanwhile, the prevalence of EPIYA types and CM sequence differ between
geographical areas. Both EPIYA motif and CM confirm their responsibility in the
downstream pathways contributing to disease progression (Hayashi et al. 2017).
CagA interacts with and alters numerous host signaling pathways in
phosphorylation-dependent and phosphorylation-independent regulated modes. It is
believed that CagA is a hub protein that mimics a tyrosine-phosphorylated host cell
protein. The phosphorylated CagA interacts with multiple cellular targets, including
Src homology 2 domain–containing protein tyrosine phosphatase (SHP2), CT10
regulator of kinase (Crk) adaptor proteins (Crk-I, Crk-II, and Crk-L), c-terminal
Src kinase (Csk), growth factor receptor–boundprotein2(Grb2),andAbelson
(ABL1) tyrosine-protein kinase. These interactions can enhance the disruption of
adherens junction structure and induce cell elongation and scattering “hummingbird
Helicobacter pylori Virulence Factors, Pathogenicity, and Gastric Cancer 125
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phenotype” (Fig. 1) (Yong et al. 2015; Takahashi-Kanemitsu et al. 2020;Salvatori
et al. 2023).
In addition to the oncogenic property of SHP2, the CagA–SHP2 interaction is of
great concern because their interactions correlate to the degree of pathogenicity
(Hayashi et al. 2012). The activated SHP2 induces an abnormal mitogenic response
through the activation of the Ras/ERK signaling pathway, which in turn promotes
the nuclear translocation of SHP2 (Alipour 2021). In the nucleus, SHP2 enables
the tyrosine dephosphorylation of parafibromin (or CDC73), mediating the
parafibromin/β-catenin complex formation, which enhances the activation of Wnt
target genes (a result of canonical Wnt signaling cascade activation). β-catenin is a
key target of the canonical Wnt signaling pathway that plays a vital role in tissue
homeostasis and embryonic development. In addition, CagA–SHP2 complex can
dephosphorylate and deactivate FAK, promoting the hummingbird phenotype.
Moreover, the interaction with Csk can also phosphorylate and inhibit Src family
kinase (SFK) activity. The inhibited SFK alters the phosphorylation status of actinbinding proteins resulting in cell motility. Since Csk is a negative regulator for Src,
the latter primarily phosphorylates CagA; thus, a negative feedback loop can control
the phosphorylated CagA and attenuate the magnitude of SHP2 deregulation by
CagA. It is hypothesized that this mechanism is the cause of the prolonged existence
of H. pylori in the stomach without symptoms (Higashi et al. 2004; Hatakeyama
2014).
Moreover, the CagA-binding host protein, SHIP2, an SH2 domain–containing
phosphatidylinositol 5′-phosphatase interacted with CagA in a tyrosine
phosphorylation–dependent manner. In contrast to SHP2 that strongly binds to
EPIYA-D, SHIP2 binds more strongly to the Western CagA-specific EPIYA-C seg-
ment. The CagA- SHIP2 interaction tethers the attachment of H. pylori to the host cell
membrane, through the alteration of the plasma membrane phosphatidylinositol
compositions, consequently, the enhancement of CagA delivery and binding to the
prooncogenic SHP2 (Fujii et al. 2020).
The non-phosphorylated CagA interactions are widely implicated in epithelial cell
proliferation, proinflammatory processes (Suzuki et al. 2009), disruption of cell–cell
junction (Amieva et al. 2003 ), and cell polarity (Saadat et al. 2007). Non-phosphorylated
CagA– mediated β-catenin activation via the CagA interaction with E-cadherin activates
and deregulates the PI3K/Akt and Wnt/β-catenin signaling pathways.
The CagA interaction with E-cadherin leads to the dissociation of β-catenin from
the E-cadherin/β-catenin complex. Thus, β-catenin is accumulated in the cytoplasm
and the nucleus, potentiating the Wnt/β-catenin signaling cascade. Dysregulation of
the Wnt/β-catenin signaling cascade is widely implicated in gastric cancer (White
et al.
2012).
CagA interacts and deregulates c-Met receptor tyrosine kinase through the CM
motif, thus activating the PI3K/Akt pathway and further inhibiting downstream
β-catenin degradation and activating Wnt/β-catenin pathway (Hatakeyama 2014;
Suzuki et al. 2009). Moreover, Tabassam et al. concluded that, similar to VacA,
CagA was responsible for GSK-3β inactivation via the PI3K/Akt signaling cascade
and downstream β-catenin activation (Tabassam et al. 2009).
126 A. M. Elgohary et al.
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In addition, non-phosphorylated CagA interacts with Grb2, the only reported host
factor that can interact with phosphorylated and non-phosphorylated CagA . This interaction stimulates the Ras/MEK/ERK pathway resulting in cell scattering and proliferation (Mimuro et al. 2002). It is reported that CagA is required to activate nuclear factor
NF-κB. NF-κB is a master that orch estratesthe immune and inflammatory responses and
plays a vital role in many processes in carcinogenesis, including transformation, proliferation, angiogenesis, and metastasis (Hirata et al. 2006; Yong et al. 2015).
2 Concluding Remarks
The gastrointestinal tract can be colonized by millions of bacteria, including
H. pylori. H. pylori are one of the most common bacteria, which accompanied
humans above 100,000 years and infect half of the human population worldwide.
Although H. pylori infection is commonly related to gastric cancer, its persistence
entails a combination of environmental, host genetic, and bacterial shape and
structure. Improper dietary and low sanity environments are the main environmental
risk factors. The modulation of the bacterial shape from spiral to coccoid forms
enhances the bacterial invasiveness in the gastric microenvironment.
H. pylori can combat the harsh acidic environment in the stomach by urease
activity and sense their way for nutrients using their flagella and chemotactic system.
However, its outer membrane proteins hinder them from being removed and support
their severe virulence. VacA and CagA are essential virulence factors that maintain
H. pylori’s persistent infection and chronic inflammation. The VacA hexameric
oligomers bind and are inserted into the lipid membrane through the formation
of anion-selective membrane channels. VacA induces multiple cellular alterations
involving different cellular sites, including the plasma membrane, mitochondria, and
endosomes. Furthermore, the presence of combined VacA alleles (s1, m1, i1, d1, and
c1) is highly associated with the increasing risk of gastric cancer. CagA interacts
with many host signaling pathways in a phosphorylated and non-phosphorylated
manner, with subsequent disruption of adherens junctions of epithelial cells and
induction of oncogenic factors transcription.
Acknowledgments Prof. Dr. Wael Elshemey is appreciated for his guidance. Dr. Abdo Elfiky is
thankful for his valuable discussions and support.
Ethics Approval and Consent to Participate Not applicable.
Competing Interests The authors declare that they have no competing interests.
Authors’ Contributions A.E. is in charge of the overall direction and designed the framework.
A.E. and N.G. drew the figure. All authors draft and approve the final version of the manuscript.
Funding No funding resources were received.
Helicobacter pylori Virulence Factors, Pathogenicity, and Gastric Cancer 127
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Gastric Cancer and Helicobacter pylori
https://t.me/med1917
Irena Mladenova
Abstract
Gastric cancer is the second leading cause of cancer mortality after lung cancer.
More than 90% of the tumors are adenocarcinomas. Approximately 5.5% of
malignancies worldwide are attributable to inflammation caused by Helicobacter
pylori. It is one of the most common infectious agents in humans and infects more
than 50% of the world’s population. This bacteria was classified as a group I
carcinogen in 1994 by the International Agency for Research on Cancer (IARC)
and the World Health Organization (WHO). Approximately 2% of H. pylori-
positive individuals develop gastric cancer. It has been shown that H. pylori
eradication therapy reduced the incidence of gastric cancer in high-risk areas.
Discoverers R. Warren and B. Marshal received the Nobel Prize in Medicine and
Physiology in 2005. The scientists have demonstrated the ability of H. pylori to
penetrate normal, metaplastic, and neoplastic gastric epithelium in vivo, intracellu-
larly and interstitially, causing an immune inflammatory response that promotes
gastric carcinogenesis. Recently, an increasing incidence of gastric cancer was
observed in younger individuals in some countries, highlighting the need for more
preventive strategies in younger populations. H. pylori also develops another
neoplastic process in the stomach, primary lymphoma, which has a significantly
better prognosis than carcinoma. Almost all patients with MALT lymphoma are
H. pylori-positive, and H. pylori-positive individuals are significantly more likely
to develop gastric MALT lymphoma. In the early stages, low-grade MALT
lymphomas can be treated with H. pylori eradication in 60–80% of cases.
I. Mladenova (*)
Medical Faculty, Department of Hygiene, Epidemiology, Microbiology, Parasitology and
Infectious Diseases, Trakia University, Stara Zagora, Bulgaria
e-mail: imladenova@yahoo.com
#
The Author(s), under exclusive license to Springer Nature Switzerland AG 2022
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2022_31
Published online: 6 October 2022
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