Comprehensive insight into altered host cell-signaling cascades upon Helicobacter pylori and Epstein–Barr virus infections in cancer

Abstract

Cancer is characterized by mutagenic events that lead to disrupted cell signaling and cellular functions. It is one of the leading causes of death worldwide. Literature suggests that pathogens, mainly Helicobacter pylori and Epstein–Barr virus (EBV), have been associated with the etiology of human cancer. Notably, their co-infection may lead to gastric cancer. Pathogen-mediated DNA damage could be the first and crucial step in the carcinogenesis process that modulates numerous cellular signaling pathways. Altogether, it dysregulates the metabolic pathways linked with cell growth, apoptosis, and DNA repair. Modulation in these pathways leads to abnormal growth and proliferation. Several signaling pathways such RTK, RAS/MAPK, PI3K/Akt, NFκB, JAK/STAT, HIF1α, and Wnt/β-catenin are known to be altered in cancer. Therefore, this review focuses on the oncogenic roles of H. pylori, EBV, and its associated signaling cascades in various cancers. Scrutinizing these signaling pathways is crucial and may provide new insights and targets for preventing and treating H. pylori and EBV-associated cancers.

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Vol.:(0123456789)
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Archives of Microbiology (2023) 205:262
https://doi.org/10.1007/s00203-023-03598-6
MINI REVIEW
Comprehensive insight intoaltered host cell‑signaling cascades
uponHelicobacter pylori andEpstein–Barr virus infections incancer
DharmendraKashyap1· SamikshaRele1· PranitHemantBagde1· VaishaliSaini1· DebiChatterjee2·
AjayKumarJain2· RajanKumarPandey3· HemChandraJha1,4
Received: 7 March 2023 / Revised: 22 May 2023 / Accepted: 23 May 2023
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023
Abstract
Cancer is characterized by mutagenic events that lead to disrupted cell signaling and cellular functions. It is one of the
leading causes of death worldwide. Literature suggests that pathogens, mainly Helicobacter pylori and Epstein–Barr virus
(EBV), have been associated with the etiology of human cancer. Notably, their co-infection may lead to gastric cancer.
Pathogen-mediated DNA damage could be the first and crucial step in the carcinogenesis process that modulates numerous
cellular signaling pathways. Altogether, it dysregulates the metabolic pathways linked with cell growth, apoptosis, and DNA
repair. Modulation in these pathways leads to abnormal growth and proliferation. Several signaling pathways such RTK,
RAS/MAPK, PI3K/Akt, NFκB, JAK/STAT, HIF1α, and Wnt/β-catenin are known to be altered in cancer. Therefore, this
review focuses on the oncogenic roles of H. pylori, EBV, and its associated signaling cascades in various cancers. Scrutiniz-
ing these signaling pathways is crucial and may provide new insights and targets for preventing and treating H. pylori and
EBV-associated cancers.
Communicated by Yusuf Akhter.
Samiksha Rele, Pranit Hemant Bagde and Vaishali Saini have
contributed equally to this work.
Extended author information available on the last page of the article

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Graphical abstract
Keywords Cancer· Helicobacter pylori· Epstein–Barr virus· Signaling· DNA damage· RAS-MAPK
Introduction
Epstein–Barr virus (EBV) is a human pathogen involved in
various tumorigenesis events such as nasopharyngeal carci-
noma (NPC), Hodgkin's lymphoma (HL), Burkitt's lymphoma
(BL), and gastric cancer (GC). The prevalence of EBV is about
90% among the human adult population. A study reported that
8.77% of GC patients were EBV-positive (Fig.1A) (Tavakoli
etal. 2020). Commonly, EBV infection does not cause any
unfavorable effects on human health until a balance between
the host and virus is sustained. EBV genome persists in epi-
somal form; once human immune surveillance machinery is
compromised, latent EBV can be reactivated to induce abnor-
mal proliferation and transformation of host cells, eventu-
ally leading to malignancy (Kashyap etal. 2021). EBV is a
DNA virus having two genome clusters that encode around
25 microRNAs that disturb the normal functioning of healthy
cells (Zheng 2010). EBV encodes a viral oncogene LMP1
(latent membrane protein-1 or BZLF1 (BamHI Z fragment
leftward open reading frame 1), essential for B cell transforma-
tion and disrupted cellular signal transduction (Siegler 2003).
Although the EBV nuclear antigen 1 (EBNA1) is the earli-
est reported viral protein post-infection and is the only latent
protein consistently expressed in virus-associated tumors,
recent results indicate that EBNA1 is not a viral oncoprotein
(Siegler 2003; Humme etal. 2003; Frappier 2012). BARF1
(BamHI-A reading frame1) is also an early gene but express
as a latent gene in most NPCs (Hutajulu etal. 2010). Recent
studies have suggested that BARF1 may have an essential role
in NPC oncogenesis (Hutajulu etal. 2010; Young and Dawson
2014). Latent membrane protein LMP1 is produced by the
BNLF1 gene, which contains C-terminal activating regions
(CTAR1, CTAR2, and CTAR3) domains (Zheng 2010; Lo
etal. 2020). These domains induce viral effect by targeting
several signaling pathways, including nuclear transcription
factor kappaB (NFkB), Delta-Notch, Renin-angiotensin sys-
tem (RAS), mitogen-activated protein kinase (MAPK), sig-
nal transducer and activator of transcription 3 (STAT3) and
phosphatidylinositol-3 kinase (PI3K) (Zheng 2010; Kung and
Raab-Traub 2008; Jakhmola and Jha 2021). EBV-associated
oncoproteins play an active role in the apoptotic inhibition
of cancer cells by secreting survivin and rendering the pro-
apoptotic protein Protease-activated receptor 4 (PAR4). EBV
also inhibits apoptosis by increasing the expression of the anti-
apoptotic gene B cell leukemia/lymphoma2 protein (BCL2)
(Kung and Raab-Traub 2008; Sun etal. 2015). Studies revealed

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enhanced survivin levels in gastric carcinoma cell lines by
LMP2A through an NFκB-mediated pathway (Kung and Raab-
Traub 2008; Pei etal. 2016). LMP1 and 2 also stimulate the
CD40 and B cell receptors (BCRs), respectively. However,
EBNA1, 2, 3A, 3B, 3C, and one leader protein EBNA-LP are
also encoded by the EBV and promote the oncogenic trans-
formations through various host proteins like E2F6 and E2F1
(Pei etal. 2020a; Hooi etal. 2017). EBNA1, nucleolin, and
nucleophosmin are crucial for EBV DNA replication and per-
sistence. Moreover, EBNA2 and LP synergistically activate
the transcription of viral and cellular genes, which can trans-
form the EBV-exposed B cells into lymphoblastoid cell lines
(LCLs). Moreover, EBNA3A, 3B, and 3C are similar in their
genetic structure and promoter and regulate the transcription
of host genes.
Helicobacter pylori (H. pylori) is a Gram-negative, micro-
aerophilic, and spiral bacterium. Human chronic H. pylori
infection strikes about 4.4 billion people globally, and its
prevalence varies geographically from 28 to 84% (Hooi etal.
2017). Moreover, group-1 carcinogen has potential to cause
cancer and H. pylori is also declared as a group-1 carcino-
gen, which cause gastric cancer (GC) in only 2% of infected
individuals (Conteduca etal. 2013). A systematic review and
meta-analysis revealed that approximately 90% of GC patients
are H. pylori positive (Fig.1B) (Lu etal. 2022). H. pylori con-
tains flagella and produces urease enzymes, which help avoid
harsh environments and enhance survivability (Dunne 2014).
They established their infection by breaching the mucous lin-
ing of the stomach. H. pylori Cag pathogenicity island-encoded
cytotoxin-associated antigen A (CagA) is a crucial factor for
inflammatory stress within gastric mucous lining and oncogen-
esis. Nonetheless, H. pylori also encode another virulence fac-
tor, vacuolating cytotoxin A (VacA), which can predominantly
induce cellular damage (Huang etal. 2016). H. pylori can also
promote oncogenic transformation by inducing epigenetic alter-
ations, viz. histone modification and DNA methylation.
Notably, the coinfection of EBV and H. pylori reduces the
time span and promotes the aggressiveness of GC (Singh and
Jha 2017). Study by Mulherkar etal. (2022) reported that the
coinfection of retroviruses such as HIV-1 and HTLV-1 has
implications for cancer malignancies. Another study by Shi
etal., revealed that the coinfection of EBV and human papillo-
mavirus (HPV) causes NPC in the endemic region. This study
reported the coexistence of these two pathogens in the human
host and its consequences towards malignancy. The coopera-
tion between these two pathogens provides the cellular milieu
for the growth and replication of each other. This study also
shows that coinfection with H. pylori and EBV enhances tis-
sue damage by the recruitment of immune cells (Al Moustafa
etal. 2009). Nonetheless, more studies need to be conducted to
understand the insight into molecular mechanisms controlling
the interplay between these two pathogens. Herein, we provide
the status of signaling pathways modulated by H. pylori and
EBV and their further consequences in cancer development.
Fig. 1 Incidence of individual
infection of H. pylori and
EBV in gastric cancer (GC). A
Showing the total number of
incidences of GC, and among
that 90% of GC are H. pylori
positive (Tavakoli etal. 2020).
Meanwhile B graph depicts the
total number of GC cases, and
among that 8.77% of GC are
EBV positive (Lu etal. 2022).
Source: A Lu etal. (2022).
Source: B Tavakoli etal. (2020)

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Role ofEpstein–Barr virus andHelicobacter
pylori inamendments ofhost cell signaling
pathways
Janus kinase/signal transducer andactivator
oftranscription pathway
EBV
The Janus kinase (JAK) and STAT play an important func-
tion in inflicting the host's immune response. This path-
way is controlled by an array of regulatory proteins, such
as the suppressor of cytokine signaling (SOCS), protein
tyrosine phosphatases (PTPs), and protein inhibitors of
activated STAT (PIAS) (Seif etal. 2017). JAK/STAT path-
way gets hyperactivated in the presence of several patho-
gens. For instance, LMP1, LMP-2A, and LMP-2B interact
with JAK3, which leads to the activation of the STAT3
pathway in diffused large B cell Lymphoma (Bousoik and
Montazeri Aliabadi 2018). A study by Kilger etal. showed
that endogenous LMP1 interacts with JAK3 in the EBV-
immortalized cell line LCL 1852.4 and HEK293 cells
upon ectopic expression. The interaction between the two
proteins enhances the tyrosine phosphorylation of JAK3,
which needs a proline-rich motif and the surrounding
LMP1 33bp repeat region sequence (Gires 1999). Sub-
sequently, the signal gets transmitted to STAT and acti-
vates certain cytokine receptors. Thus, this pathway leads
to the upregulation of HLX expression, which diminishes
NKX6-3, SPIB, IL4R, and BCL2L11 to interfere with cell
differentiation and subdue cell apoptosis (Luo etal. 2021).
In cancerous cells, JAK/STAT helps to escape immune
surveillance by increasing the expression of programmed
cell death ligand-1 (PD-L1) (Green etal. 2010). LMP1
also utilized the NFκB-dependent interferons to regulate
the STAT1 pathway (Najjar etal. 2005). Notably, inter-
ferons are a crucial component of the host defense system
which protects against pathogenic viruses by activating the
innate and adaptive immune systems. Interferons (IFNs)
can activate JAK/STAT pathways by binding to cognate
receptors (Michaud etal. 2010). In response to Interferon-
gamma (IFNy), EBNA1 increases the phosphorylation of
STAT1 and enhances the STAT1 expression in cancer cell
lines (Najjar etal. 2005; Michaud etal. 2010). Interfer-
ons like IFN2 and IFN7 negatively regulate the EBV Qp
promoter, whereas IFN1 and IFN2 can positively regulate
it. Regulation of Qp is essential for EBV pathogenesis.
Activation of STAT1 by LMP1 encompasses a media-
tor like IFNy, which is secreted in an NFκB-dependent
manner (Luo etal. 2021; Moon etal. 2017; Wood etal.
2007). LMP1 also induces various chemokines like IP10,
RANTES, and MIP1α (Vaysberg etal. 2009). The JAK/
STAT pathway is always active during EBV latency along
with STAT3, STAT4, and STAT5 (Wang 2016). CTAR3,
the domain of LMP1, which resides between CTAR1 and
CTAR2 domains, has been reported to show its binding
activity with JAK3 and activate STAT1 (Dunne 2014;
Vaysberg etal. 2009). This particular domain has been
recently found to interact with UBC9, inducing SUMOlya-
tion of IRF7 (Vaysberg etal. 2009; Wang 2016). Interest-
ingly, higher IFN secretion and SOCS3 suppression were
caused by EBV-infected monocytes, which further ampli-
fied IFN secretion. As mediated by JAK/STAT pathway,
EBV blocks this pathway by IRF7, which was demon-
strated by siRNA-suppressed SOCS3. Besides, EBNA1
knockdown reduced the expression of JAK2 and STAT1
signaling by a reduction in the activity of IFNγ-induced
PD-L1 promoter (Moon etal. 2017; Ersing etal. 2013).
H. pylori
Helicobacter pylori induces the production and secretion
of growth factors and pro-inflammatory cytokines, which
activate the STAT3 and tend to cause GC (Menheniott etal.
2015). STAT3 controls various cellular processes, viz.
basal homeostasis, angiogenesis proliferation, and apopto-
sis. It also gets activated by the phosphorylation of receptor
tyrosine kinases, including JAK1, JAK2, and Src (Ersing
etal. 2013; Menheniott etal. 2015). The H. pylori genome
consisting of a 40-kb DNA fragment (known as cag PAI)
encodes ~ 30 genes. One of these ~ 30 genes, the CagA
gene, encodes the cagA protein, which is responsible for
virulence. Intriguingly, infection of CagA-positive strains
is related to a higher risk of gastric cancer. Activating the
STAT3 pathway in cagA-dependent manner tends to trigger
gastritis and ultimately cancer (Piao etal. 2016; Hatakeyama
2014). The Type 4 secretion system (T4SS) aids CagA to
dock with the inner plasma membrane, thereby causing its
delivery inside the epithelial cells. The phosphorylation of
this protein occurs on C-terminal EPIYA (Glu-Pro-Ile-Tyr-
Ala) motifs. Depending on adjacent amino acids, different
EPIYA motifs are recognized and designated EPIYA-A to
D (Piao etal. 2016). Several mouse model studies suggest
that cagA triggers signal transduction via IL11 and IL6 by
utilizing glycoprotein-130 (gp130), while IL11 activates
gastric STAT3. Therefore, it can be corroborated that IL11-
dependent activation may occur in the early stage of this
pathway (Yin etal. 1950). Moreover, both recruitment
and homo-dimerization of gp130 are induced by IL6. This
potentially leads to a balance between the signaling of both
JAK/STAT and SHP2/Ras/ERK pathways. Disrupting this
signal transduction in the mutant mouse with gp130 knock-
in mutation induces the formation of premalignant lesions,
including atrophy, mucous metaplasia, and dysplasia, even-
tually leading to gastric cancer. Furthermore, ligand binding

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forms a signal transduction pathway wherein phosphoryla-
tion causes activation of gp130-associated JAK kinases and
STAT3 (pTyr705). After its dissociation and dimerization,
pSTAT3 moves to the nucleus, initiating gene transcription
and targeting the expression of downstream effector genes
that lead to cell survival, proliferation, angiogenesis, inva-
sion, and migration (Yin etal. 1950).
Studies based on human gastric adenocarcinoma cells
(AGS) revealed that phosphorylation of cagA preferen-
tially activated SHP2 binding and activation of ERK. On
the other hand, unphosphorylated CagA leads to the activa-
tion of STAT3 (Menheniott etal. 2015). In non-gastric tis-
sues, H. pylori-induced Toll-like receptor manifest signaling
through STAT3-dependent mechanisms (Tye etal. 2012).
STAT3 causes upregulation of TLR2 gene expression, as
observed in an IL11/STAT3-dependent mouse model of gas-
tric cancer. Ablation of TLR2 does not affect inflammation
but blocks tumor growth. In the immune pathologies of H.
pylori, IL17 is involved in neoplastic growth that sets off
chronic inflammation. Triggering the STAT3 pathway by
H. pylori-induced IL23 secretion from dendritic cells results
in increased prevalence and production of mucosal TH17
cells and pro-inflammatory IL17 cytokines (Menheniott
etal. 2015). In addition, IL22 responses are mediated via its
heterodimeric receptor complex (IL22R), composed of two
subunits, IL10R2 and IL22R1. IL22 and its receptor form a
complex that leads to the activation of STAT3 that further
mediates an immunoregulatory effect on human gastric epi-
thelial cells infected by H. pylori (Fig.2) (Ersing etal. 2013;
Tye etal. 2012; Chen etal. 2014).
Interferon regulatory factor signaling pathway
EBV
Mammalian interferon regulatory factors (IRFs) comprise
nine members, namely IRF19. One of the factors, IRF7, is
known for its post-translational phosphorylation and ubiq-
uitination properties. Receptor-interacting protein kinase
1 (RIP1) and tumor necrosis factor receptor (TNFR)-
associated factors (TRAF6) are important proteins that
contribute to LMP1-mediated activation of IRF7 (Ning
etal. 2011) SUMOylation of this pathway is carried for-
ward by the physical interaction of ubiquitin-conjugating
enzyme 9 (UBC9) and CTAR3 domain of LMP1 (Bentz
etal. 2012). Through the C-terminal domain, LMP1 acti-
vates a multitude of transduction events (Wang 2016;
Ning etal. 2011). Along with the C-terminal functional
domain, the activator regions 1 and 2 of the C-terminal
are required to activate IRF7 (Ning etal. 2011). LMP1
induces an upsurge in the transcriptional activity of IRF7
via phosphorylation (Bentz etal. 2012). The viral pro-
tein leads to deubiquitylation of interferon via A20 to
repress its activity (Bentz etal. 2012). In EBV latency III,
Fig. 2 Signaling pathways associated with H. pylori infection leading
to oncogenic transformation of cells. H. pylori triggered the various
host cell signaling pathways to transform the normal gastric epithe-
lial cells into the gastric cancer (GC). Notably, H. pylori modulate
the TNF Receptor-Associated Factor 2 (TRAF2), epidermal growth
factor receptor (EGFR), mitogen-activated protein kinase kinase
(MAPKK), Just Another Kinase (JAK), signal transducer and activa-
tor of transcription 3 (STAT3), β-catenin, nuclear factor kappa beta
(NFkB) pathways to promotes the inflammation, cell proliferation,
cell survival, invasion and alleviated the programmed cell death

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LMP1 introduces covalent modifications in IRF7 (Bentz
etal. 2012). LMP1 uses small ubiquitin-related modifi-
ers 1 (SUMO1) and FLAG-SUMO1 to SUMOylate IRF7
(Bentz etal. 2012). IRF7 in turn controls the expression
of LMP2 (Brennan etal. 2001; Sgarbanti etal. 2007).
There have been reports of gene overlapping between
LMP1 targeted modification of the IRF7 pathway and
NFκB pathway, indicating that the two pathways may
cooperate during EBV infection. LMP1 activates IRF4
but does not interfere with the expression of IRF2 (Ning
etal. 2011). Notably, siRNA-mediated suppression of
c-Myc leads to reduction of ZEBRA and EBV early
antigen, thereby inhibiting EBV reactivation (Gao etal.
2004). Antiapoptotic episomal maintenance of EBV is
majorly due to EBNA1 which was inhibited by siRNA
targeting endogenous EBNA1. This led to a reduction in
tumorigenesis (Yin and Flemington 2006). RIG-1 target-
ing siRNA was used to elucidate the function of miR-
BART6 that triggers IFN-β during EBV infection to evade
immune surveillance (Lu etal. 2017). As miRs interfere
with host gene expression, EBV miRs have been reported
to indirectly target type 1 IFN pathways through TLR7
and TLR9 (Bouvet etal. 2021). Genome-wide CRISPR/
Cas9 loss-of-function screening identified that LMP1
leads to cFLIP induction, which is critical against TNFα-
mediated cell death (Ma etal. 2017).
H. pylori
TLR7, 8, or 9 activation leads to an increase in type I inter-
feron production in response to bacterial DNA or single-
stranded RNA ingestion via phagosome. Inflammatory
cytokines and type I interferons are transactivated by various
factors such as NFκB, activator protein 1 (AP1), and IRF3/7.
During H. pylori infection, activation of IRFs occurs through
DC-SIGN receptors through an unidentified route (Sonkar
etal. 2020). Retinoic acid-inducible gene I (RIG-I) and other
RIG-I-like receptors (RLRs) are activated by 5' triphosphate
(PPP) single-stranded RNA, which causes a conformational
shift that activates tank-binding kinase 1 (TBK1). This ulti-
mately results in the generation of type I interferons through
the IRF3/7 signaling (Cheok etal. 2022).
H. pylori infection of gastric epithelial cells results in a
wide range of intricate host protective immunological reac-
tions. Type I interferon is produced by the nucleotide-bind-
ing oligomerization domain 1 (NOD1) signaling pathway,
which drives chemokine and cytokine responses that control
the severity of gastric H. pylori infection (Watanabe etal.
2011). Stomach adenocarcinoma (STAD) subgroup analyses
based on race, gender, age, H. pylori infection status, his-
tological subtypes, tumor grade, specific cancer stages, and
nodal metastasis status revealed the increased expression of
IRF3/7. Hence, the study revealed that only in 5–6% of all
Fig. 3 Outcomes of the altered signaling pathways in during H. pylori
infection. The most important outcomes of H. pylori infection are
gastritis or malignant transformation in abut 2–3% of infected popula-
tions. During the malignant transformation H. pylori altered the vari-
ous host signaling pathways to promote the cell proliferation, inflam-
mation, ROS generation, angiogenesis, and metastasis. Besides, H.
pylori also disturbed the hemostasis between cell proliferation and
apoptosis which leads to accumulation of cells

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STAD patients, IRF3 and IRF7 were found to be altered.
Additionally, IRF7 is strongly correlated with immune infil-
tration in STAD and is associated with the expression of
the majority of immunological biomarkers as well as the
number of immune cells (Guo etal. 2021). The activation of
heterotrimeric transcription factor complexes known as IFN-
stimulated gene factor 3 (ISGF3) and subsequent production
of CXC motif chemokine ligand 10 (CXCL10) and type I
IFN occurs as a result of IRF7-induced IFN beta production.
Nonetheless, Watanabe etal. (2010) revealed that
NOD1-deficient mice lacking the IFN beta receptor showed
a reduced CXCL10 response and elevated susceptibility
to H. pylori infection. STAT1 and IFN regulatory factor
1 (IRF1) are the two elements of the IFN signaling path-
way, which gets stimulated through the direct effects of H.
pylori, leading to increased proinflammatory signaling in
epithelial cells through the activation of the NOD1 pathway.
It has been reported that H. pylori-mediated activation of
the NOD1 pathway increases STAT1-Tyr701/Ser727 phos-
phorylation levels and IRF1 expression/synthesis in a cell,
leading to increased production of the chemokines, which
are controlled by NOD-1, IFNγ-, IL8- and IFNγ-induced
protein 10 (IP10). As a result, H. pylori-induced inflamma-
tory responses are influenced by the interaction between
NOD1 and IFNγ signaling pathways, potentially revealing
a new mechanism by which H. pylori strains promote severe
illnesses (Allison etal. 2013) (Fig. 3). NOD1 enhances
mucosal host resistance against H. pylori infection by acti-
vating type I IFN signaling pathways and producing AMPs.
Intracellular NOD1 sensing of H. pylori-derived PGN in
gastric ECs triggers production of type I IFN and CXCL10
via the RIP2-TRAF3-TBK1-IKKε-IRF7-ISGF3 pathway,
promoting Th1 responses. Because IFNγ generated by Th1
cells increases NOD1 expression. During prolonged H.
pylori infection, the type I IFN-CXCL10-IFNγ axis caused
by NOD1 activation provides a positive feedback loop for
the development of Th1 responses in the stomach mucosa
(Minaga etal. 2018). The number of H. pylori organisms
colonizing the stomach was lower in wild-type mice than
in IFN gamma knockout (IFN−/−) mice (Sawai etal. 1999;
Kong etal. 2020).
Nuclear factor kappa B pathway
EBV
NFκB tunes various host cellular processes like immune and
inflammatory responses, transformation, proliferation, angi-
ogenesis, and metastasis. Suppression of NFκB activation
is known to reduce the oncogenic potential of transformed
cells (Ma etal. 2017; Sonkar etal. 2020). The canonical and
non-canonical NFκB pathways are recognized as being of
utmost importance. Notably, LMP1 activates the canonical
NFκB pathway (Vaysberg etal. 2009; Cheok etal. 2022).
The N-terminal tail of LMP1 is composed of 24 amino acid
residues, while the C terminal domain houses 200 residues
along with six transmembrane domains. The TES1 domain
starts from residues 187–231, and the TES2 domain spans
residues 351–386 of LMP1. LMP1 uses the TES2 domain to
mediate the activation of the canonical pathway and TES1
to activate the non-canonical pathway (Ersing etal. 2013).
TES2 activates TRAF6 and leads to CTAR2-mediated
pathway activation (Watanabe etal. 2011; Guo etal. 2021;
Sethi etal. 2008). Proteins like BEX3, BEX5, and BS69
are essential to link LMP1 and TES2 to TRAF6 to activate
the NFκB pathway (Hayden and Ghosh 2012; Schultheiss
2001) Apart from TRAF6, IRAK1 is also used to activate
the NFκB pathway (Ersing etal. 2013; Gewurz etal. 2012;
Luftig etal. 2003). The expression of EGFR activated by
LMP1-CTAR1 provides a novel system to assess the contri-
bution of NFκB pathway activation (Kung and Raab-Traub
2008). Increased glucose uptake is a prerequisite for cellular
growth in B-cell lymphomas; this increased uptake is altered
by LMP1-mediated NFκB, causing dysregulation of glucose
transporter protein type 1 (GLUT1). Moreover, TES2 also
upregulates several inhibitors of NFκB regulators, including
ABIN1, CYLD, A20, RNF11, TAX1BP1, and IκBα (Ers-
ing etal. 2013; Gewurz etal. 2011). Nonetheless, siRNA
analysis of kinases identified that NFκB essential modifier
(NEMO) is among the strongest inhibitors of LMP1 that
further activate canonical NF-κB activation (Boehm etal.
2010).
H. pylori
Pathogens like H. pylori are known to modulate the level
of NFκB through TLR activation and by other host onco-
proteins. H. pylori alters the canonical and non-canoni-
cal pathways of NFκB activation depending on specific
cell types (Lamb and Chen 2010). In epithelial cells, H.
pylori activate the canonical NFκB cascade, whereas in
B-lymphocytes it activates both pathways. Nonetheless,
the binding of ligands with their receptor activates the
kinase complex IκB kinase (IKK) (Lamb and Chen 2013).
IKK in turn triggers the translocation of the canonical
NFκB heterodimer of p50 and RelA/p65 and encour-
ages the breakdown of inhibitor IκB phosphorylation.
Canonical and non-canonical NFκB pathways differ in
the signaling mechanism. However, the exact mecha-
nisms of the NFκB non-canonical pathway are yet to be
understood. Associated H. pylori LPS can activate this
pathway in B-lymphocytes through the NFκB-inducing
kinase (NIK) and IKK (Sun 2011). The receptor's down-
stream signaling activates the NIK and IKKα. Activated
IKKα phosphorylates its downstream p100, which later
induces the proteasomal degradation of p52 (Chen 2005).

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RelB and p52 work together to form a transcriptionally
active complex that turns on the target genes involved in
lymphoid organogenesis, B cell survival, maturation, and
bone metabolism (Lamb and Chen 2013). In addition to
LPS and peptidoglycan of H. pylori, other virulence genes
also trigger the activation of NFκB. The multimerization
of cagA also has a vital role in NFκB activation through
the Met-PI3K-Akt pathway. CagA interacts with intram-
embrane hepatocyte growth factor receptor (HGFR)/MET
in gastric epithelial cells to initiate PI3K-Akt signaling,
which activates β-catenin and NFκB. Nonetheless, cagA
activates TGF-β-activating kinase 1 (TAK1) by interact-
ing with TRAF6 and TAK1. TAK1 later phosphorylates
and activates the IKK complex leading to the activa-
tion of NFκB (Lamb and Chen 2013). Moreover, Hirata
etal. (2006) showed that siRNA-mediated knockdown
of NOD1 or RIP2 expression had no effect on H. pylori-
induced NFkB/MAPK activation or CXCL8 synthesis in
AGS cells. OMVs (Outer membrane vesicles) isolated
from H. pylori activate NFkB in AGS cells, in a cagPAI-
independent way. Interestingly, siRNA suppression of
NOD1 expression prevented CXCL8 synthesis in AGS
cells exposed to H. pylori-derived OMVs (Minaga etal.
2018).
c‑Jun proto‑oncogene signaling pathway
c‑Jun pathway andEBV
TRAF2, along with other proteins, mediates the activation of
JNK (Liu etal. 1996; Vanden Berghe etal. 1998). Proteins
involved in LMP1-mediated activation of the JNK pathway
include TAK1/TAB1, TRAF6, c-Jun N terminal kinase 1, 2,
and TRAF6. The proteins mentioned above further recruit
CTAR2 to activate the JNK pathway and also bridge the gap
between TAB1 and LMP1 (Wu etal. 2006; Wan etal. 2004).
The presence of 379PVQLSY384 motif on the C terminal
of LMP1 establishes its interaction with TRAF6; this is why
TRAF6 is an essential protein in activating this pathway
(Wan etal. 2004). Receptor-interacting proteins (RIP) are
also involved in the activation of the JNK pathway (Gewurz
etal. 2011; Boehm etal. 2010). SEK1 kinase upstream of
JNK is required for LMP1-mediated activation of JNK by
TES2. JNK phosphorylation occurs with the help of BZLF1
and BRLF1, which further activates ATF2 (Mosialos 2001;
Adamson etal. 2000). BGLF2, the tegument protein along
with BNRF1, also plays a role in the phosphorylation of
the JNK pathway, which in turn activates the BZLF1 (Liu
and Cohen 2016). LMP1 expressing primary tumor cells
derived from PTLD biopsies and EBV-transformed B cells
survive and proliferate due to the IKK2–TPL2–JNK pathway
Fig. 4 Altered signaling pathways during EBV infection leading to
oncogenic transformation of cells. Similarly, EBV also promotes the
oncogenic transformation of gastric epithelial and B cell by altering
the various host cell signaling pathways. The most important path-
ways utilized by the EBV to promotes the cancer are hypoxia-induci-
ble factor1-α, nuclear factor kappa beta (NFkB), Just Another Kinase
(JAK), signal transducer and activator of transcription 3 (STAT3),
interferon regulatory factor 7(IRF-7), B cell receptor (BCR), Trans-
forming growth factor beta (TGF-β), mitogen-activated protein
kinase, phosphatidylinositol-3 kinaseand PI3 kinase (PI3K), and pro-
tein 38

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(Voigt etal. 2020). The proteins that are important in LMP1-
mediated activation of the JNK pathway are TRAF6, TAK1/
TAB1, JNKK1, JNKK2, RIP, IKK2, NEMO, TES2/CTAR2,
SEK1, IL1, IL5, TNIK, and TPL2 (Fig.4).
c‑Jun pathway andH. pylori
H. pylori induces apoptosis signal-regulating kinase 1
(ASK1) in gastric epithelial cells in a reactive oxygen spe-
cies (ROS) and cagPAI-dependent manner. JNK activation
and H. pylori-mediated apoptosis are governed by ASK1
(Hayakawa etal. 2013). Early JNK activation and cytokine
production driven by H. pylori are mediated through the
transforming growth factor (TGF-β)-activated kinase 1
(TAK1). Whenever TAK1 or downstream p38 MAPK is
inhibited, ASK1 is activated by the formation of ROS, and
TAK1 is suppressed, which results in downstream NFκB
activation in H. pylori-related responses (Hayakawa etal.
2013). H. pylori infection activates new signaling pathways
like ROS/ASK1/JNK, which governs apoptotic cell death
(Wen etal. 2018a). The fate of epithelial cells infected with
H. pylori may rely on the balance of ASK1-induced apop-
tosis and TAK1-induced antiapoptotic or inflammatory
responses, which may play a role in the etiology of gastri-
tis and gastric cancer (Hayakawa etal. 2013). Thioredoxin
(TRX), a protein that modulates reduction and oxidation,
binds to ASK1 directly, and intracellular ROS can activate
ASK1 by releasing it from TRX (Saitoh 1998). Through
the phosphorylation of the MAP2Ks, MKK4, and MKK3,
ASK1 activates the downstream MAPKs, JNK, and p38.
Numerous human disorders involve the activation of ASK1
and subsequent MAPK. As a result, ASK1 is crucial for
the emergence of colitis, colon cancer, liver damage, liver
cancer, and gastric cancer (Hayakawa etal. 2011). TAK1
controls JNK activity both positively and negatively in a
ROS-dependent manner. It also regulates ASK1 activation
negatively via binding to TAB1. In contrast, ASK1 inhib-
its the effect of TAK1 on interleukin-1β (IL1β)-dependent
NFκB activation (Hayakawa etal. 2013). ASK1 gets acti-
vated by H. pylori and regulates ROS-mediated and JNK-
dependent apoptosis, and it has a reciprocal role in gastric
cancer (Mochida etal. 2000).
Transforming growth factor‑beta cascade
EBV
The TGF-β family consists of three members found in
mammals, namely TGFβ1, TGFβ2, and TGFβ3. TGFβ
induced p15 and p21, which stops the cells from entering
the S-phase by preventing phosphorylation of tumor-sup-
pressor pRB (Kashyap etal. 2022). Marked resistance to
TGFβ1-mediated cell apoptosis is carried out by LMP1 due
to an uprise in cyclin D2 levels and by LMP2A via AKT/
PI3K pathway (Velapasamy etal. 2018). EBNA1, which is
involved in the maintenance of viral genes, upregulates and
phosphorylates STAT1 with the help of INFy and INFα in
8-azahypoxanthine-resistant epithelial cells (Ad-AH). TGF-
β1 targets ID2 which is produced by EBNA1 and activates
the Smad complex leading to an inhibition of SMAD2 by
EBNA1 (Wood etal. 2007). LMP2A, on the other hand,
eradicates the growth inhibitory effect of TGFβ by prevent-
ing Smad2 from getting phosphorylated with the help of
miR-155-5p (Liu and Cohen 2016; Shi etal. 2020). Smad2
gets destabilized by EBNA1 and LMP2A, which keeps the
inhibitory effect of TGF under check, thus favoring viral
replication and boosting the infection capacity inside the
host by increasing the expression of BZLF1 (Luo etal.
2021). LMP1 induces cancer-causing proteins like VEGF
and MMP9 (Voigt etal. 2020; Hayakawa etal. 2013; Kondo
etal. 2005). LMP1 induces its effect through the non-smad
arm of TGF signaling. In epithelial cells, LMP1 activates
TGF signaling in an NFκB-dependent manner (Morris
etal. 2016). The EBV-induced proteins essential in the
TGF pathway is smad1, 2, 4, AP-1, ID2, LMP2A, EBNA1,
LMP1, and activin A. Moreover, study also revealed that
knockdown of TGFβ by siRNA resulted in suppression of
EBV transmission (Nanbo etal. 2018).
H. pylori
TGF-β signaling contributes to the pathogenesis of H.
pylori infection (Li etal. 2015). H. pylori infection with a
cagE-positive gene upregulates the TGFβ1-mediated epi-
thelial–mesenchymal transition (EMT) pathway and conse-
quently promotes EMT (Chang etal. 2015). Furthermore,
through the TGFβ-mediated p38 MAPK signaling cascade,
the H. pylori infection reduces the expression of cystic
fibrosis transmembrane conductance regulator (CFTR) and
solute carrier family 26 member 6 (SLC26A6) in duodenal
epithelial cells. It provides insight into the pathophysiology
of duodenal ulcers linked to H. pylori (Wen etal. 2018b).
According to earlier research, TGFβ promotes H. pylori
colonization and adhesion to host cells. It has also been
linked to autoimmune disorders and gastritis, both caused
by H. pylori. The severity of H. pylori-associated with non-
metaplastic atrophic gastritis is correlated with the increased
expression of TGFβ1.
Additionally, the human gastric mucosal biopsy results
showed that TGFβ1 mRNA expression is much higher in
H. pylori-infected specimens compared to uninfected sam-
ples. The level of chronic inflammation and its impact are
both positively correlated with the VacA genotype. Through
the production of T-regs, TGFβ1 acts as a critical negative
regulator of the immune response (Wan and Flavell 2008).
Since T cell proliferation and immunological responses are

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inhibited by the H. pylori-related virulence factor vacA,
this could increase the adherence of H. pylori to the gastric
mucosa by upregulating TGFβ expression. Compared to
H. pylori-negative populations, H. pylori-infected patients
including those with gastritis and peptic ulcers have higher
serum concentrations of IL17A, IL23, and TGFβ, indicating
the degree of inflammation varies based on these cytokines
concentrations (Arachchi etal. 2017). The immunohisto-
chemical staining of TGFβ, TGFβ-RI, and Smad7 was
higher in H. pylori-positive patients compared to H. pylori-
negative patients, suggesting that the feedback loop involv-
ing TGFβ1 and Smad7 may be crucial for the development
of H. pylori infection (Li etal. 2015).
TGFβ has also been shown to promote miR-155 expres-
sion via the Smad4 pathway. SMAD2 is the major signaling
pathway downstream of TGFβ. Although the precise mecha-
nism by which miR-155 regulates inflammation by influenc-
ing SMAD2 is unknown, considering the elevated level of
TGFβ in H. pylori infection, we believe that miR-155 acts
as negative feedback to lessen the pathogenesis of H. pylori
infection (Wu etal. 2007).
Phosphatidylinositol 3‑kinase pathway
EBV
PI3K pathway is one of the majors signaling pathways
associated with various types of cancer. As an enzymatic
antagonist of PTEN, PI3K is reported to be a carcinogen in
humans and helps maintain a balance between the tumor-
suppressor genes, phosphatase and tensin homolog deleted
on chromosome 10 (PTEN) and PI3K (Kondo etal. 2005;
Pei etal. 2020b). Class I PI3K consists of p110α, p110β,
p110γ, and p110δ isoforms, products of PIK3CA, PIK3CB,
and PIK3CD (Katso etal. 2001) which gets combined with
p85 and p110 and expressed in several types of cancers
(Zhao and Vogt 2008). Previous reports unveiled that Class
II and III PI3Ks are non-carcinogenic, and it does not pro-
duce PIP3, an essential protein that controls cell growth and
replication (Zhao and Vogt 2008). The p110 domain binds
with p85 with a high affinity, and a serine/threonine protein
kinase activity occurs, which phosphorylates p85 (Dhand
etal. 1994). The product of serine/threonine kinase Akt is
responsible for the inactivation of GSK3 (Cross etal. 1995)
and also negatively impacts FOXO (Brunet etal. 1999). Inac-
tivation of GSK3 leads to disrupted regulation of cAMP
response element binding protein (CREB) and an upshot in
cyclin D1 and Myc levels (Sears etal. 2000). Akt controls
cell death by two proteins, BAD and Caspase-9, which are
crucial to induce its effects on transcription factors through
phosphorylation of BAD, caspase9, and FKHRL1 (Peso
and González-Garcıa M, Page C, 1997). Cancer causing
viruses have transformed PI3K/Akt pathway to enhance their
survival and infectivity (Engelman 2009). One such virus is
EBV which uses LMP1 and LMP2A to activate PI3K path-
way causing increased cell proliferation, genomic instability,
apoptotic inhibition, and rearrangement of the cytoskeleton
(Chen 2012). LMP1 induces secretion of IL10 in B cells via
activation of PI3K (Lambert and Martinez 2007). LMP1
inhibits DNA repair and reduction in cyclin D2 and D3 lev-
els via CTAR1-mediated activation of PI3K/Akt pathway
(Chen etal. 2008). It also inactivates FOX3a and represses
DDB1. LMP1 also indirectly affects microtubule activity by
inducing the formation of stress fiber and activating cdc2
leading to phosphorylation of Op18, which regulates cell's
entry into mitosis (Chen 2012; Lin etal. 2009). The viral
oncoprotein also inhibits the proapoptotic activity of Par4
by de novo synthesis via multiple signaling pathways (Chen
2012; Lee etal. 2009). LMP1 increases the production of
survivin through PI3K pathway to prevent apoptosis in can-
cer cell lines (Sun etal. 2015). Not only survivin but also
Bcl2 expression increases when PI3K gets activated (Lee
etal. 2009). LMP1 is associated with the p85 domain of
PI3K (Dawson etal. 2003). PI3K in turn activates the Akt
pathway, whose major role is to protect against apoptosis
by inhibiting the proapoptotic ability of molecules (Dawson
etal. 2003; Coffer etal. 1998). Once PKB/Akt is activated,
two residues, namely Thr308 within the P loop and Ser473,
get phosphorylated (Coffer etal. 1998). LMP1 leads to the
downregulation of PTEN expression by increased expres-
sion of miR-21. This further leads to the activation of PI3K/
Akt, causing the expression of cancer stem cell markers,
thereby promoting the formation of tumor clusters and can-
cer development. LMP2A protects the EBV-mediated gastric
cancer cells from the effects of chemotherapy by activating
PI3K/Akt pathway, which provides resistance to apoptosis
(Chen 2012; Shin etal. 2010). Furthermore, EBNA2 targets
the p55α subunit of PI3K and CD40 and p85 subunit used
by LMP1. Importantly, IL10 has been associated with the
maintenance of EBV latency and tumors. siRNA-mediated
IL10 knockdown prevented phosphorylation of PI3K/AKT
further causing EBV lytic replication (Gao etal. 2019). Host
miRNA-142 works in conjunction with a tumor-suppressor,
PTEN, both of which regulate the PI3K/ Akt pathway. This
pathway is suppressed due to miR-BART6-3p-mediated
downregulation of PTEN (Zhou etal. 2016).
H. pylori
AP1 is a transcription factor existing in a dimeric complex of
Jun and Fos proteins, which can be homo- and heterodimers.
These protein subunits involve Jun (c-Jun, JunB, JunD), Fos
(c-Fos, Fra1, Fra2, FosB), activating transcription factor
(ATF), and musculoaponeurotic fibrosarcoma (MAF), which
eventually regulate cell proliferation, cell cycle, and inflam-
mation (Gazon etal. 2018). To form an active transcription

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complex, homo and heterodimeric complexes are formed
with Fos, whereas c-Fos only heterodimerizes with members
of the Jun family (Ding etal. 2008). Jun and Fos dimer-
ize efficiently with several transcription factors, including
members of the ATF/CREB or Maf/Nrl families of proteins
(Mechta-Grigoriou etal. 2001). Several pathogens including
H. pylori are known to hijack the AP1 pathway.
Among the strains of H. pylori, few are highly pathogenic
due to their cagPAI. Type IV secretion system (T4SS) is
expressed due to cag pathogenicity present in the genomes
of highly virulent H. pylori strains. The T4SS form a pilus
structure for delivering the virulent factor in CagA into the
host cells achieved by several T4SS proteins that include
CagI, CagL, CagY, and CagA. These proteins bind to host
cell integrin member β1 delivering cagA across the host cell
membrane (Tegtmeyer etal. 2011). The injection process
also involves the interaction of CagA with phosphatidylser-
ine. After getting delivered into the host cell, CagA mimics
a host cell factor due to its phosphorylation by oncogenic
tyrosine kinases, which is recognized by the NOD1 and acti-
vates NFκB, MAPK, and AP1 (Allison etal. 2009).
Studies have suggested that NOD1 is critical for the acti-
vation of AP1. In siNOD1 expressing gastric epithelial cells
exposed to cagPAI+ H. pylori, a significant reduction was
observed in p38 and ERK phosphorylation. On the other
hand, there was no significant change in JNK phosphoryla-
tion. In contrast, only weak AP1 activation was observed
in wild type or an isogenic strain without the VacA gene
and isogenic strains of H. pylori with mutations in certain
Cag genes (Naumann etal. 1999). Additionally, mutations
in the CagA, Cag PAI, VacA, and non-phosphorylated CagA
showed attenuated DNA binding activity of AP1. Also, the
H. pylori flagella mutation does not affect AP1 activity. H.
pylori induces the expression of c-Jun and c-Fos in gastric
epithelial cells. The binding of these proteins to promoters
of interleukin (IL6, IL8, matrix metalloproteinase (MMP1),
cyclin D1, and cyclooxygenase2 (COX2) leads to the regula-
tion of these genes. The binding of c-Jun, c-Fos, and ATF-2
to the COX-2 promoter occurs in a MAPK-dependent man-
ner via a Toll-like receptor. This has been implicated in
COX2-mediated cancer cell invasion and angiogenesis (Ding
etal. 2008).
Besides, CagPAI activates AP1, which results in the cas-
cade of cellular kinase responses such as c-Jun N-terminal
kinase, MAP kinase 4, and p21-activated kinase, and small
Rho-GTPases including Rac1 and Cdc42. The activation of
AP1 is involved in activating pro-inflammatory cytokines/
chemokines. The H. pylori-mediated AP1 activation in gas-
tric epithelial cells (i.e., AGS and MKN45) vary increasingly
with time- and dose-dependent expression of c-Jun, JunB,
JunD, Fra1, and c-Fos proteins (Ding etal. 2008). AP1 acts
as a downstream executioner protein for mitogen-activated
protein kinases (MAPK), TGFβ, and Wnt (Jochum etal.
2001). Contrarily, AP1 also alters the extracellular signals
for genes containing AP1 binding sites in their promoter or
enhancer regions (Shaulian and Karin 2002). ERK, P38, and
JNK each selectively regulate AP1 subcomponent activity
and DNA binding activity (Ding etal. 2008). According to
Nakayama etal. (2009), a short incubation of VacA causes
β-catenin to activate and accumulate in the nucleus and is
dependent on an inactive GSK3. Additionally, prolonged
exposure to VacA causes Akt to be inactivated and GSK3 to
be activated, which subsequently downregulates β-catenin
activity. Another recent research shows that CagA adversely
controls autophagy via the c-Met-PI3K/Akt-mTOR signal-
ing pathway, which is linked to an upsurge in the release of
proinflammatory cytokines. Therefore, we hypothesizethat
CagA's suppression of autophagy promotes gastric inflam-
mation, which in turn starts the multistep process of gastric
carcinogenesis (Li etal. 2017). Meanwhile, elevated miR-
143-3p expression in H. pylori-positive gastric cancer tis-
sues and cells. In the BGC-823 GC cell model, miR-143-3p
mimics can reduce proliferation and induces apoptosis,
whereas miR-143-3p inhibitors did the reverse. Subsequent
research revealed that AKT2 modulated the effects of miR-
143-3p.(Wang etal. 2017).
Hypoxia‑inducible factor 1α pathway
EBV
The HIF1 transcription factor contains HIF1, HIF2α, and
HIF3α subunits, which are needed to accelerate the progres-
sion of cancer (Kraus etal. 2017). HIF1α can activate a
total of 60 genes including VEGF. HIF1α has a short half-
life of 5–8min (Berra etal. 2001; Zhu etal. 2016). HIF1α
mediates the change of EBV from latent to lytic phase by
activating the expression of the BZLF1 gene (Kraus etal.
2017). HIF gene products undergo degradation by prolyl
hydroxylases (PHDs) (Demidenko and Blagosklonny 2011).
It was seen that EBNA3A, 5, and LP are responsible for
rendering PHDs inactive to stabilize HIF1α (Kraus etal.
2017; Darekar etal. 2012). EBNA3A targets PHD2, and
EBNA5 attaches itself to PHD1 (Darekar etal. 2012). Due
to the blockage of PHDs, hydroxylation and degradation of
HIF1α cannot take place, and an accumulation of HIF1α
occurs. LMP1 increases the level of H2O2 which results
in the induction of HIF-1α (Kraus etal. 2017; Wakisaka
etal. 2004). Once HIF1α stabilizes, it activates GLUT1,
PDK1, and LDHA genes by forming a heterodimer with
ARNT (Darekar etal. 2012). LMP1 is not only involved
with HIF-1α activation but is also responsible for transcrip-
tional activation of VEGF to some extent aided by COX2
(Luo etal. 2021; Darekar etal. 2012; Wakisaka etal. 2004).

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Signaling pathways like p42/p44 MAPK are also involved
in enhancing LMP1-mediated HIF1α induction (Wakisaka
etal. 2004). In NPC cells, LMP1 prohibits the degrada-
tion of HIF1α with the help of SIAH1 E3 ubiquitin ligase
(Zhu etal. 2016; Kondo etal. 2006). The SIAH family of
proteins has a high level of similarity. SIAH1 and SIAH2
only differ in their NH2 terminal and are 98% identical to
one another (Hinshaw and Shevde 2019). LMP1 stabilizes
SIAH proteins, leading to the degradation of PDH1 and
PDH3 (Hinshaw and Shevde 2019). On the other hand, in
B lymphoma cells, SIAH1 expression is inhibited by LMP1
which upregulates β-catenin (Hinshaw and Shevde 2019;
Jang etal. 2005). Interestingly, Kraus etal. demonstrated
that shRNA-mediated knockdown of HIF1α reduces EBV
lytic replication. This is done as HIF1α binds directly to the
promoter of the BZLF1 gene, Zp thereby associated with
EBV related malignancies (Kraus etal. 2017). Furthermore,
knockout of p53 using CRISPR-Cas9 resulted in failure of
HIF-1α to activate Zp-promoted transcription of viral pro-
teins (Kraus etal. 2020).
H. pylori
The activation of HIF1α aids the progression of malignant
diseases, including GC. H. pylori starts the PI3K/mTOR
signaling cascade, which triggers HIF-1α and releases the
G0/G1 cell cycle arrest via CDK1. As a result, HIF1α has
been recognized as a mediator between the cell cycle arrest
signaling induced by H. pylori infection and survival (Cana-
les etal. 2017). Usually, the canonical signaling pathway
controls the expression of HIF1α through the hydroxylation
of proline 402 and 564 by utilizing the proline hydroxylases
and following the proteasomal degradation pathway. Moreo-
ver, hypoxia led to a decline in proline hydroxylase activ-
ity and elevated the HIF-1α protein (Canales etal. 2017).
HIF1α can be triggered by hypoxia and hypoxia independ-
ent processes, such as the generation of ROS, activation of
tyrosine kinase receptors, MEK/ERK, and PI3K/Akt/mTOR
pathways (Laughner etal. 2001).
In cancer cells, the half-life of HIF1α is regulated by
tumor suppressors p53 and VHL (Von Hippel–Lindau pro-
tein) (Laughner etal. 2001). Moreover, genetic alterations,
alleviated intra-tumoral oxygen, loss-of-function mutations
of VHL, p53, PTEN, and gain-of-function mutation in PI3K,
SRC, and MAP signal cascade increases the HIF1α pro-
duction (Laughner etal. 2001). HIF1α induces the VEGF
expression in 3T3 and MCF7 cells via downregulating the
expression of EGFR and PI3k/Akt pathway (Laughner
etal. 2001; Wang etal. 2014). Precisely, gastric epithe-
lial cells exposed to H. pylori stabilize the HIF1α through
PI3K/Akt/mTOR activation, leading to GC (Canales etal.
2017). The elevation in AQP3 expression through activat-
ing the ROS pathway in the stomach may be a mechanistic
component of H. pylori-infection-mediated carcinogenesis
(Wen etal. 2018a). Through the ROS, HIF1α, and AQP3
axis, AQP3 can mediate ROS uptake and speed up intracel-
lular ROS deposition, which aggravates AQP3 expression.
Since human gastric cancer cells are encouraged to migrate
and proliferate when aquaporin3 (AQP3) is overexpressed,
AQP3 may play a significant role in the development of gas-
tric carcinoma.
BCR signaling pathway
EBV
LMP2A mimics a B cell receptor in many ways starting
from the pathways through which signal gets delivered to
the tyrosine-based motifs in respective domains and trigger-
ing similar downstream signaling pathways just like the B
cell receptor (Mancao and Hammerschmidt 2007). LMP2A
and LMP1 are responsible for modulating the B cell recep-
tor (BCR) pathway (Mrozek-Gorska etal. 2019). Igβ and
Igα are the components that help to mediate signaling to
BCR (Dykstra etal. 2001). There are several ways by which
LMP2A inactivates this pathway, which leads to the inhibi-
tion of lytic signaling (Mancao and Hammerschmidt 2007;
Brinkmann and Schulz 2006; Radolf and Samuels 2021).
Several models have been hypothesized on how LMP2A
downregulates BCR signaling. One of them considers the
eradication of PTK and Syk by LMP2A from BCR and the
inhibition of downstream effectors like PRKCD from getting
phosphorylated by tyrosine (Brinkmann and Schulz 2006).
Moreover, other researchers discuss how LMP2A restricts
BCR from interacting with lipid rafts (Brinkmann and
Schulz 2006). The immunoreceptor tyrosine-based activa-
tion motifs on B cells inhibit BCR signaling (Brinkmann and
Schulz 2006). Erk1 is involved with the phosphorylation of
S15 and S102 residues of LMP2A (Brinkmann and Schulz
2006). This pathway is involved with the demethylation of
DNA and reactivation of EBV via activation of TPA, which
eventually leads to binding between Tet1 and Zta promoter
(Fig.5) (Zhang etal. 2016). Furthermore, study revealed
that Bruton’s tyrosine kinase (BTK) is a key component
involved in BCR signaling. BTK knockdown with siRNA
block BCR signaling thus involved in BCR mediated lytic
induction (Kosowicz etal. 2017). Additionally, host miR-
141 is exploited by EBV to mimic viral miR and block BCR
signaling to promote lytic replication of the virus (Chen
etal. 2021).
H. pylori
H. pylori can cause persistent infection due to its ability to
hijack the host's immune response. BCR signaling is one of
the crucial pathways identified in tumorigenesis. Diverse

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BCR activation mechanisms exist, ranging from a chronic
antigenic drive by microbial or viral antigens, B cell auto-
stimulation by self-antigens to activating mutations in intra-
cellular components of this pathway. H. pylori infection is
associated with the development of lymphomas of mucosa-
associated lymphoid tissue (MALT) (Niemann and Wiest-
ner 2013). Development of non-Hodgkin lymphomas occurs
from nodal and extranodal lymphoid tissues. The marginal
zone (MZ) of MALT is associated with a distinct subset
of extranodal lymphomas. The number of microbes asso-
ciated with such lymphomas is increasing with increased
molecular investigations comprising members such as H.
pylori, C. jejuni, B. burgdorferi, C. psittaci, and hepatitis
C virus (HCV). These microbes have been associated with
gastric lymphoma, immunoproliferative small intestinal dis-
ease, cutaneous lymphoma, ocular lymphoma, and spleen
lymphoma, respectively (Suarez 2006). Studies have also
demonstrated that in the case of gastric diffuse large B cell
lymphoma (DLBCL), regression has been observed after
eradication of H. pylori, but if the disease is unresponsive
to H. pylori eradication, then DLBCL can progress rapidly.
Hence, H. pylori eradication has become a primary thera-
peutic target for gastric DLBCL. Gene expression analy-
sis shows a reduced expression of B cell signaling-related
genes and increased tumor microenvironment-related genes
indicating a positive association in response to H. pylori
eradication (Torisu etal. 2021).
Mitogen‑activated protein kinase pathway
EBV
The mitogen-activated protein kinase/extracellular sig-
nal regulated protein kinase (MAPK/ERK) pathway or
Ras–Raf–MEK–ERK pathway involves a chain of proteins
communicating with cell surface receptors to the nucleus.
MAPK regulates various processes like proliferation, apop-
tosis, differentiation, and transformation in higher organ-
isms (Zhang and Liu 2002). Mainly in mammals, three types
of MAPK families have been discovered, which include
classical (ERK), p38 kinase and c-Jun N-terminal kinase/
stress-activated protein kinase (JNK/SAPK) and ERK5 (Luo
etal. 2021; Zhang and Liu 2002). The enzymes linked to
the MAPK pathway are MAPKKK, MAPKK, and MAPK
(Zhang and Liu 2002). LMP1 can activate the ERK path-
way (Roberts and Cooper 1998). ERK pathway gets acti-
vated when Thr202 and Tyr204 undergo phosphorylation
(Chen etal. 2002; Payne etal. 1991). Due to the presence of
vimentin, LMP1 can interact with several cellular signaling
pathways (Roberts and Cooper 1998). Such interactions of
the oncogene with MAPK pathways result in tumorigenesis.
Fig. 5 Outcomes of the altered signaling pathways in during EBV
infection. EBV promotes the lytic replication, immune evasion, cell
proliferation, epithelial-to-mesenchymal transformation, and metas-
tasis to promote the oncogenic transformation. Moreover, during the
oncogenic transformation EBV also utilized the various signaling
molecules such as adaptor protein 1 (AP-1), programmed cell death
ligand 1 (PD-L1), nuclear factor kappa beta (NFkB), c-Jun, signal
transducer and activator of transcription 3 (STAT3) and beta catenin
(β-catenin)

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The pathway undergoes a 3.8- to 5.0-fold rise in activity,
which results in the proliferation of B cells (Roberts and
Cooper 1998). LMP1 also reduces the expression of dual-
phosphatase DUSP6 and DUSP8 (Lin etal. 2020). Inter-
action of MAPK with EBV oncogene not only results in
proliferation and enhanced cell resistance to chemotherapy
but also benefits the virus in replication and increases its
infectivity by enabling the expression of BZLF1 and BGLF2
(Luo etal. 2021). BZLF1 is an indicator of EBV reactivation
(Liu and Cohen 2016). The micro-RNA-BART22 of EBV
also targets MAP3K5, which results in EMT and inhibition
of cell apoptosis (Luo etal. 2021). For LMP2A, it is still
unclear how it interacts with the MAPK pathway. However,
it has been deduced that LMP2A indirectly uses the MAPK
pathway to send proliferation signals to B cells (Liu and
Cohen 2016; Anderson and Longnecker 2008). Besides,
the p38 signaling pathway also plays a vital role in EBV-
mediated cancer progression and metastasis. Importantly
CTAR1 and CTAR2 mediated by TRAF2 are responsible for
the activation of the p38 pathway (Eliopoulos etal. 1999).
If the p38 pathway is inhibited, it affects the LMP-mediated
expression of IL6 and TNF-mediated NFκB expression
negatively (Eliopoulos etal. 1999; Eliopoulos etal. 1999).
Inhibition of p38 also leads to apoptosis and further inhibits
the reactivation of EBV in Raji cells (Matusali etal. 2009).
The gene bzlf1 expression gets inhibited along with the
inhibition of p38 phosphorylation (Matusali etal. 2009).
Other proteins that are targeted by the p38 pathway include
hsp27, Elk1 (Raingeaud etal. 1996), ATF2 (Eliopoulos etal.
1999; Raingeaud etal. 1995), CHOP/GADD153 (Eliopoulos
etal. 1999; Wang and Ron 1996), and MAX30 (Eliopoulos
etal. 1999; Zervos etal. 1995). In addition to CTAR1 and
CTAR2, TAK1 is also required to activate the p38 path-
way (Wan etal. 2004). Since p38 is activated in response to
stimuli like stress or perhaps an initial infection, transient
overexpression of LMP1 in response to p38 may prevent the
cells from going through apoptosis. An indirect phospho-
rylation cascade involving the substrates MAPKAP-2 and
MSK1 allows both p38α and p38β to activate CREB and
ATF1 phosphorylation. The primary activating transcription
factor that binds CRE in LMP1 is the ATF1-CREB heterodi-
mer. Notably, siRNA-mediated knockdown of p38 MAPK
prevents the LMP1-mediated thymidine phosphorylase (TP)
induction and thus promotes the apoptosis and reduced the
chances of cancer progression (Chen etal. 2002).
H. pylori
H. pylori are known to take over this pathway and result in
cytokine production. In contrast, MAPK inhibitor treatment
showed mitigation in the H. pylori-stimulated chemokines in
the gastric cells (Seo etal. 2004). MAPK gets activated by
the action of Ras and Raf proteins and directly upregulates
ERK. At least two transcription factors, c-Myc, and Elk-1,
are phosphorylated by specific ERK proteins that are acti-
vated by MEK and translocate to the nuclei (Chen 2006).
H. pylori secretions have direct proliferation-stimulating
effects through the MAPK pathway on gastric epithelial cells
(Chen 2006). Additionally, H. pylori utilize T4SS to trans-
locate peptidoglycan, which gets detected by the pathogen
recognition protein NOD1, leading to NFκB activation. A
significant decrease in p38 and ERK phosphorylation was
seen in siNOD1-expressing cells driven by CagPAI+ H.
pylori (Allison etal. 2009). The amount of IL8 produced
by H. pylori considerably decrease through the suppression
of p38 and ERK activity (Allison etal. 2009). By phospho-
rylating IKKβ and cytosolic phospholipase A2 (cPLA2), H.
pylori LPS activates ERK, which increases NFκB nuclear
translocation and induces the production of COX2 and iNOS
(Slomiany 2012). The cells of the immune system like neu-
trophils, monocytes, and mast cells are triggered by the H.
pylori neutrophil-activating protein (HP-NAP), which acts as
a virulence factor. In human neutrophils, HP-NAP induces
ERK and p38-MAPK activation, while the c-Jun N-termi-
nal kinase does not (Nishioka etal. 2003). Additionally, H.
pylori stimulated serum-responsive element (SRE)-depend-
ent gene transcription and elevated c-Fos protein expression,
demonstrating the signaling mechanism through which H.
pylori activates ERK (Chen 2006).
Wnt/β‑catenin pathway
EBV
Differentiation and proliferation of mammalian cells involve
the Wnt/β-catenin signaling pathway and have been linked
to numerous cancers. Hence, this pathway is important for
development, tissue homeostasis, and disease (Zwezdaryk
etal. 2016). A multifunctional protein β-Catenin is critical
for this signaling pathway, and the stabilization of this pro-
tein is disrupted due to mutations in numerous carcinomas.
β-Catenin undergoes rapid degradation in type I B-lympho-
cytic lines but is stable in type III B cell lines. In contrast,
its transcriptional activity is significantly higher in type III
B cells. The association of β-catenin with deubiquitinating
enzymes might be critical for its stabilization. Activation of
this signaling pathway during EBV infection might contrib-
ute towards the characteristic lymphoproliferation of type III
latency (Shackelford etal. 2003). Viral modulation of these
cellular processes is increasingly interesting in understand-
ing cancer development. Viruses interact with the Wnt path-
way through numerous mechanisms, including epigenetic
modifications, miR targeting, and altering signaling mem-
bers, leading to nuclear translocation of β-catenin, thereby

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activating downstream signaling. Modulating this signaling
pathway could be an approach for initiating and maintaining
viral pathogenesis, resulting in virus-induced cancers due to
dysregulation (Luo etal. 2021; Zuylen etal. 2016). Notably,
oncogenic host miR-4721 modulates PI3K/Akt/c-Jun path-
way further leading to Wnt/ β-catenin-mediated tumorigen-
esis as a result of induction by EBV-miR-BART22 (Tang
etal. 2020).
H. pylori
The canonical Wnt pathway or Wnt/β-catenin pathway leads
to the activation of T cell factor/lymphocyte enhancer fac-
tor (TCF/LEF) families of transcription factors via accu-
mulation of β-catenin in the cytoplasm (Pai etal. 2017).
Upstream stimulus triggers dissociation of β-catenin from
degrading complex due to attachment of Wnt to its mem-
brane receptor, namely Frizzled, and a co-receptor lipopro-
tein receptor-related protein 5/6 (LRP5/6) (Song etal. 2015).
Subsequently, β-catenin escapes the degradation process due
to phosphorylation by glycogen synthase kinase 3β (GSK3β)
and the ubiquitin-proteasome system (UPS). This leads to
the accumulation of β-catenin in the cytoplasm that is fur-
ther translocated into the nucleus to combine with TCF/LEF.
Contrarily, the anomaly in activating this pathway leads to
cell proliferation and cell malignant transformation (Song
etal. 2015). Certain pathogens like H. pylori also modu-
late the Wnt/β-catenin pathway through secreted glycopro-
teins Wnt1 and Wnt3a, leading to cancer-like pathologies.
Besides, H. pylori causes activation of the Wnt/β-catenin
pathway majorly via two gateways, c-Met and EGFR signals
(Soutto etal. 2015).
The c-Met receptor gets activated in several cancers,
such as gastric and colorectal cancer and further leads to
activation of the phosphatidylinositol 3-kinase (PI3K)/Akt
signaling. PI3K/Akt eventually triggers the accumulation
of β-catenin in the cancer cells. Activating the PI3K/Akt
pathway promotes cell proliferation, invasion, and escape
from the apoptotic pathways. In contrast, c-Met inactivation
accelerates GSK3β activity and degradation of β-catenin.
Also, augmented c-met expression due to β-catenin suggests
positive feedback between c-Met and β-catenin in cancer-
ous cells (Song etal. 2015). Unlike c-Met, H. pylori acti-
vate EGFR signaling through VacA, CagE, CagL, secretory
protein HP0175, and outer inflammatory protein A (OipA)
but not CagA. Intriguingly, CagA inactivates the EGFR by
binding to SH2 domain-containing protein tyrosine phos-
phatase (SHP-2). Further, the H. pylori factors induce EGFR
phosphorylation, eventually leading to PI3K/Akt pathway
activation.
EGFR-PI3K/Akt gives a suppression signal to GSK3β;
thus, β-catenin gets accumulated (Soutto etal. 2015). Once
activated, Akt further activates or inhibits downstream target
proteins through phosphorylation, including GSK3β, NFκB,
p21, etc. (Geng and Zhang 2017). H. pylori activates the
PI3K pathway in a CagPAI-dependent manner. OMP outer
inflammatory protein A (OipA) is also involved in the activa-
tion of AKT and phosphorylation of GSK3β. H. pylori also
lead to the activation of PI3K and AKT in an Src and EGF
receptor-dependent manner (Nagy etal. 2009). Apart from
this, H. pylori activate this pathway through extracellular
UreB, which binds to TLR 2 receptor in the gastric epithelial
apical membrane (Toh and Wilson 2020). Even though H.
pylori induce activation of the PI3K pathway, and the infec-
tion leads to opposite effects in gastric cells, like cell cycle
arrest in the G1 phase and cell death by apoptosis (Canales
etal. 2017). PI3K/AKT/GSK3β signal pathways might regu-
late the proliferation of gastric cancer cells (Geng and Zhang
2017). Constant activation of PI3K due to H. pylori infection
might contribute to the development of gastric cancer (Peek
and Crabtree 2006). N24P55γ, the regulatory subunit of
PI3K, potentially inhibits the proliferation of gastric cancer
cells and promotes apoptosis (Geng and Zhang 2017). VacA
stimulates the activity of protein kinase B (PKB) by PI3K
activation. This results in increased GSK3 phosphorylation
that further releases β-catenin from the GSK3β/β-catenin
complex translocating it to the nucleus. This whole process
leads to the activation of the promoter of cyclin D1.
Furthermore, Runx3, a tumor-suppressor gene, usually
undergoes downregulation in gastric cancer cells because
of promoter hypermethylation. Runx3-mediated suppres-
sion of the Wnt/β-catenin pathway is reported when ternary
complex forms in association with β-catenin/TCF4. The
Runx3 loss increases the expression of Wnt/β-catenin genes
and induces gastric carcinogenesis (Soutto etal. 2015). H.
pylori virulence gene CagA through the WW domain gets
associated with the PY motif of Runx3 and results in the
ubiquitination and degradation of Runx3. Yet another factor
trefoil factor 1 (TFF1) usually expresses in gastric mucosa
but downregulates in gastric cancers due to mutations in the
hypermethylation gene. Infection of H. pylori may lead to
hypermethylation of TFF1. In the H. pylori-positive mucosa,
TFF1 was found to be decreased and methylated compared
to H. pylori-negative mucosa. TFF1 reduces the nuclear
translocation of β-catenin by inhibiting the phosphoryla-
tion of both Akt and GSK3β through protein phosphatase
2A (PP2A) (Soutto etal. 2015). The ablation of TFF1
elevates H. pylori-induced β-catenin activation with onco-
genic potential (MacDonald etal. 2009). H. pylori products
involved in virulence include urease, OipA, the neutrophil-
activating protein NapA, adhesins, heat-shock protein, and
lipopolysaccharide.
The infection of H. pylori recruit’s macrophages via
monocyte chemoattractant protein-1 (MCP-1) or Sonic

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Hedgehog (Shh) on gastric mucosa and secrete several
proinflammatory cytokines (Oshima etal. 2011). In gas-
tric cells, TNF-α potentially activates the Wnt/β-catenin
signaling via Akt-GSK3β activation. In colon cancers,
macrophage-derived IL1β inhibits GSK3β activity and
degradation of β-catenin, enhancing TCF (T-cell factor)
transcription activity (Oshima etal. 2011). The GSK3β
suppression by IL1β depends on the activation of NFκB
and Akt. Macrophages are also involved in cholangiocar-
cinoma, where they are involved in the activation of the
Wnt/β-catenin pathway (Boulter etal. 2015). These obser-
vations identify macrophages as critical linkers between
chronic inflammation and Wnt/β-catenin activation (Soutto
etal. 2015).
Toll‑like receptor signaling pathway
EBV
The antiviral responses of both infected cells and respond-
ing immune system cells are directly regulated by Toll-
like receptors (TLRs). As a result, they are essential for
responses against the related murine virus MHV68, onco-
genic γ-herpesviruses (EBV), and Kaposi’s sarcoma-associ-
ated herpesvirus (KSHV), which directly infect the immune
system cells (Sun etal. 2016). However, these viruses can
also lead to infections that last for a lifetime. TLRs may
also regulate inflammation during latent infection and aid
in developing tumors brought on by viruses. These viruses
may re-enter the replicative lytic cycle post-TLR activation
(Gaglia 2021).
TLR9 can recognize EBV and activate innate immune
responses, which may help to regulate the spread of the
virus and the development of latently infected B cells. EBV
may manipulate the host immune system by interfering with
TLR9 expression and function to promote the long-term sur-
vival of the virus. TLR9 activation by bacterial, viral, or par-
asitic DNA may affect the growth of EBV-infected B cells
and the equilibrium between latent and lytic EBV. TLR9
signaling in EBV-infected B cells may be advantageous for
the host and the highly adapted human gamma-herpesvirus
(EBV) (Zauner 2012). The development of systemic lupus
erythematosus (SLE, often known as lupus) is associated
with TLR7's abnormal activation. TLR7 is also engaged in
the host’s innate immunity against pathogens. The expres-
sion of EBV LMP1 and IRF7, which are involved in the
stimulation process, gets upregulated by TLR7 activation.
TLR7 activation does not cause IFNs to be produced by
EBV-infected cells, but it does make them more susceptible
to TLR3 or TLR9 activation, which can cause IFN produc-
tion. LMP1 and IFNs are co-expressed in the same cells in
some lupus patients. Therefore, LMP1-expressing cells may
release IFNs in lupus patients due to the abnormal activa-
tion of TLR7. These findings suggest that EBV may con-
tribute to some lupus patients by enhancing IFN production
(Valente etal. 2012). Knockdown of TLR3 by siRNA leads
to a reduction in EBER1-induced IFN indicating the role of
EBER1 in viral pathogenesis and immune invasion (Iwakiri
etal. 2009).
H. pylori
Multiple H. pylori antigens including LPS, flagellin A, etc.,
can activate TLR2, 4, 5, 8, and 9. MyD88 is identified to be
a major protein in TLR signaling via induction of IRAK1
and TLR4 and subsequently NFκB and AP1 with numerous
targets including IL6 (Pachathundikandi etal. 2013). Toll-
like receptors (TLRs) are known to play important roles in
gastric carcinogenesis. The signaling pathway starts with
establishing antigen-specific immune responses against
the pathogen-associated molecular patterns (PAMPs) of H.
pylori. Likewise, chronic inflammation produces damage-
associated molecular patterns (DAMPs) that may contribute
to the development of gastric cancer (Uno 2014). Further,
the extracellular domains of TLRs consist of leucine-rich
motifs like PAMP proteins that lead to ligand binding. The
cytoplasmic tail of TLR proteins has identified homology
to the IL1 and IL18 receptors; thereby, it can trigger the
intracellular signaling pathways via several adapter proteins
(Su etal. 2003). These adaptor proteins include myeloid
differentiation factor 88 (MyD88), toll-interleukin 1 recep-
tor (TIR) domain-containing adapter protein (TIRAP),
toll interacting protein (TOLLIP), (IRAK), (TRAF), TIR
domain-containing adapter inducing interferon (IFN)-beta
(TRIF), and TRIF-related adapter molecule (TRAM) (Uno
2014).
Besides, the TLR signaling works in both MyD88-
dependent and MyD88-independent manner. The MyD88-
dependent pathway gets activated by a different range of
TLRs, namely TLR1, 2, 4, 5, 6, 7, and 9. After getting a
signal from TLRs, MyD88 recruits various molecules,
including IRAK1, IRAK4, and TRAF6, to the TLR-MyD88
complex. This further causes phosphorylation of IRAK1 and
TRAF6, thereby phosphorylating multiple adaptor molecular
complexes downstream to MAP kinases-AP1 complex and
IKK complex NFκB (Uno 2014). On the other hand, the
MyD88-independent pathway is associated with the activa-
tion of TL3 or TLR4 that induces IFNβ-mediated responses.
The independent pathway involves propagating intracellu-
lar signals by TRIF and TRAM adaptor molecules, which
consequently activate the IKK pathway, thereby producing
IFNβ (Uno 2014).
Helicobacter pylori also activate TLR pathways and
induce inflammation by producing proinflammatory
cytokines, chemokines, and ROS, which form tumor

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microenvironment like gastric carcinogenesis (Uno 2014).
LPS derived from H. pylori is considered a direct stimu-
lator of TLR4, induces the NFκB pathway, and eventually
promotes the production of proinflammatory cytokines as in
the IL8 pathway. H. pylori-inflamed cells show an increase
in TLR4 expression on the apical site of gastric epithelial
cells in contrast to the basolateral site (Maeda etal. 2001).
Moreover, the NAP has also been reported to work as a
ligand of TLR2 via DAMP recognition (Ding etal. 2005).
Besides, the H. pylori flagellin recognized by TLR5 triggers
IL8 secretion via p38 MAP kinase, while TLR9 recognizes
unmethylated CpG DNA and produces type- I IFN, IL6 and
IL12 (Andersen-Nissen etal. 2005).
Role ofMicroRNAs (miRs) intheregulation
ofH. pylori andEBV infection
EBV
MicroRNAs (miRs) exist in a wide spectrum of organisms
including eukaryotic and viral genomes. miRs are of various
lengths in between 20–25 nucleotides, which regulate the
oncogenic processes (Kuroda etal. 2005; Noto etal. 2013).
The viral miRNAs are known to interact with both host
and viral mRNAs. These miRNAs bind to the 3’ untrans-
lated region by getting incorporated into the RNA induced
silencing complex (RISC) (Cullen 2009). This can plausibly
either lead to suppression of translation or degradation of
the mRNA. Viral miRs have been observed to evade the
host immune system and lead to enhanced tumorigenicity
as they aid in maintaining viral latency by targeting the host
or the EBV genes (Kim etal. 2017). pri-miR-BHRF1, 2, and
3 encoded by EBV gene BHRF1 promote viral propagation
as they favor lytic replication through the proliferation of
virus-infected cells (Seto etal. 2010).
Suppression of host immune responses occurs as miR-
BART6-3p targets the RIG1 gene (Lu etal. 2017). This miRs
also regulates signaling in NFκB and PI3K/Akt pathways
as it carries the potential to target PTEN and IL6R in Bur-
kitt lymphoma cells (Ambrosio etal. 2014). Suppression of
cellular immunity occurs when IFNγ and STAT1 are tar-
geted by viral miRNAs, miR-BART20-5p and miR-BART8
(Huang and Lin 2014). Another miRNA, miR-BART16,
leads to the inhibition of IFN signaling via targeting cAMP
binding protein (CBP) in virus infected B cells and epithelial
cells (Hooykaas etal. 2017).
EBV escapes the host immune system by its ability to
exploit the host miRs. A latent EBV protein, EBNA2, leads
to subsequent downregulation of MyD88 and IRAK1 as the
Fig. 6 Role of miRNAs in EBV and H. pylori infection. Impor-
tantly, H. pylori and EBV also regulate the various host micro-
RNAs (miRs). The modulation in the expression of miRs leads to
altered homeostasis of various host signaling pathways and aggres-
sive malignant transformation. H. pylori and EBV so far known to
altered the B cell receptor (BCR), interleukin-1 receptor-associated
kinase 1 (IRAK-1), transforming growth factor beta (TGF-β), phos-
phatidylinositol-3 kinaseand PI3 kinase (PI3K), nuclear factor kappa
beta (NFkB), Just Another Kinase (JAK), signal transducer and acti-
vator of transcription 3 (STAT3), interferon gamma (IFN-y) and beta
catenin (β-catenin) signaling pathways to disturbed the homeostasis
and enhance the malignant transformation

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viral protein causes upregulation of miR-21. Generally, miR-
155 leads to the stabilization of persistent viral infection
by attenuating NF-κB signaling. Activation of host NFκB
signaling and miR-155 majorly occurs due to enhanced
expression of viral LMP1 in virus-infected B-cells (Lu etal.
2008). This host miRNA also suppresses the JAK/STAT
signaling by targeting the SOCS1 (Jiang etal. 2010). EBV-
infected cells are observed to have high levels of SOCS1
due to upregulated miR-155 (Delgado-Ortega etal. 2013).
miR-BART3 and miR-BART5, which are upregulated dur-
ing EBV infections, were predicted to be potential targets of
genes like p53, TGFβ, and the ones involved in Wnt sign-
aling. This leads to the modulation of transformation and
apoptosis in NPC carcinoma cells (Wan etal. 2015). EBV
miRNAs promote EMT due to the activation of β-catenin
by inhibiting E-cadherin and β-TrCP (Wang etal. 2019).
Notably, Wang etal. (2022) reported that PD-L1 expression
is also enhanced by the EBV-encoded miR-BART17-3p due
to FOXP1 inhibition resulting in escalated tumor immune
escape. Meanwhile, EBV-encoded EBERs are known to
upregulate host miR-190 that prevent apoptosis, thereby pre-
serving type 1 latency of the virus.(Lyu etal. 2014). Cellu-
lar miRNAs such as miR-93 and miRNA-19a are involved in
the disruption of TGF-β signaling, thereby promoting EBV
mediated oncogenic progression. (Lyu etal. 2014) (Fig.6).
H. pylori
Altered expression of miRNAs is also reported in H. pylori-
associated GC (Hayashi etal. 2013). H. pylori elevate the
miR-21, miR-155 and miR-222 and downregulates the
expression of mir-124a, miR-320, miR-101, miR-203 miR-
210 (Song etal. 2015). H. pylori strain 7.13 downregulates
the expression of miR320, which further regulates the
expression of Mcl1-mediated apoptosis (Noto etal. 2013).
Notably, compared to Cag− strains, the Cag+ strain causes
markedly greater levels of Mcl1. Consequently, H. pylori-
mediated apoptosis via miR-320 in a Cag-dependent manner
induces activation of the Wnt/β-catenin signaling pathway
(Noto etal. 2013). The Wnt signaling pathway is widely
known for its role in embryogenesis and carcinogenesis. H.
pylori, along with TNFα induces up-regulation of WNT10A
and causes aggressive GC through Wnt/β-catenin/TCF sign-
aling pathway (Kirikoshi etal. 2001). Notably, 20–30% of
GC shows the nuclear accumulation of β-catenin (Song etal.
2015). Additionally, H. pylori infection may activate the
Wnt co-receptor LRP6, which results in the accumulation
of β-catenin in the nucleus (Song etal. 2015). The methyla-
tion patterns were discovered to correlate positively with
H. pylori infection. Additionally, the hypermethylation of
the promoters SFRP4 and SFRP5 has commonly led to the
downregulation of Wnt antagonists in GC. H. pylori-medi-
ated GC also expresses Wnt3 along with Wnt7a, Wnt7b, and
Wnt receptor frizzled (Song etal. 2015). Through the activa-
tion of the WNT/β-catenin/TCF signaling pathway, H. pylori
may play an important role in human gastric cancer (Kiriko-
shi etal. 2001). Exon 3 of the β-catenin gene, which codes
for the serine-threonine phosphorylation sites for GSK3β,
has certain mutations that prevent UPS from degrading the
protein. The β-catenin degradation complex gets disassem-
bled due to recurrent downregulation of APC expression
in colon cancer. Unlike colon cancer, APC mutation and
methylation are not involved in gastric cancer (Franco etal.
2005). In contrast to Cag− or uninfected individuals, H.
pylori Cag+ specimens showed increased nuclear β-catenin,
which is mainly localized in epithelial cells inside the prolif-
erative zone in antral glands (MacDonald etal. 2009).
The role of MDM2 in the potential regulatory mecha-
nisms of H. pylori LPS induced miR-375 and miR-106b
expression has been explored and it can boost the expression
of JAK1 and STAT3. Interestingly, in GC cells, JAK2 has
been identified as a direct target gene of miR-375. LPS from
H. pylori may activate the JAK/STAT signaling pathway
in gastric epithelial cells by inhibiting miR-375 and miR-
106b (Ye etal. 2015). This led to increased Bcl2 expression,
which consequently encouraged the proliferation and car-
cinogenesis of gastric epithelial cells produced by H. pylori.
The first miRNA studied in humans was miRNA lethal7
(let7). Let7b, which binds to the 3′-UTR regions of TLR4
mRNA and typically inhibits its activity at a post-transcrip-
tional level, has been linked to the initiation of immunologi-
cal responses in addition to its many roles in carcinogenesis.
Infection with H. pylori reduces let7b levels, which increases
TLR4 expression and activates NFkB, eventually resulting
in inflammation (Săsăran etal. 2021). In case of H. pylori
infection, miRNA-155 appears to be implicated in a nega-
tive feedback system by attenuating the NFkB response and
reducing the production of pro-inflammatory cytokines such
as IL8 (Tang etal. 2010; Ceppi etal. 2009). As a result of H.
pylori infection, miRNA-146 was also shown to be a nega-
tive modulator of IL8, growth-related oncogene (GRO)-α,
and macrophage inflammatory protein (MIP)-3α via the
same NFkB pathway (Liu etal. 2010). miR-21 is a post-
transcriptional suppressor of PDCD4, a protein that activates
NFkB and suppresses IL10 production. As a result, miR-
21 boosts IL10 levels and blocks NFkB, limiting inflam-
mation (Sheedy etal. 2010). H. pylori infection promotes
upregulation of miR-21 in gastric epithelial cells, and its
persistence in the setting of GC implies that this pathogen
disrupts the proliferation/apoptosis balance (Zhang etal.
2008). Several miRs have been reported to be up-regulated
in gastric carcinomas; the question of their dysregulation in
gastric epithelial cells during H. pylori infection is apparent.
Zhang etal. (2008) showed a connection between H. pylori
infection and miR-21. Petrocca etal. (2008a, 2008b) showed
that miR-106b, miR-93, and miR-25 alter the physiological

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response of GC cells to TGFβ, influencing both the cell
cycle and apoptosis. MiR-30a-3p and miR-30a-5p levels
were considerably lower in H. pylori-infected MKN45 cells,
miR-30a-3p could reduce COX-2 expression and β-catenin
nuclear translocation. β-catenin impaired the function of
TCF/LEF promoter targeting BCL9 to alter downstream tar-
get gene expression, therefore controlling the proliferation
and migration of H. pylori-infected gastric GC (Liu etal.
2017). H. pylori infection also reduced miR-27b expression,
and frizzled class receptor 7 (FZD7), a key receptor for the
Wnt/β-catenin signaling pathway, was identified as a direct
target gene of miR-27b. Overexpression of miR-27b inhib-
ited GC cell proliferation and Wnt signal pathway activation
caused by H. pylori, whereas FZD7 reversed these effects
(Geng etal. 2016) (Fig.6).
Coinfection ofH. pylori andEBV ingastric cancer
Reports show that non-malignant gastroduodenal disorders
(NMGDs) coinfection with EBV and H. pylori was present
in 34% of cases (Dávila-Collado etal. 2020). Comparing
studies where EBV infection was directly tested in stomach
specimens to studies where EBV infection was established
by serological methods, a greater coinfection rate (EBV + H.
pylori) was identified. There were no studies comparing the
coinfection rate in NMGDs with that in asymptomatic peo-
ple despite the fact that the majority of these research was
conducted in Latin America and India and most of them
compared NMGDs with GC (Dávila-Collado etal. 2020).
Coinfection of H. pylori and EBV also decreases the onset of
GC (Rihane etal. 2020). Furthermore, a study by Kashyap
etal. shows that prior exposure of H. pylori produced the
cellular milieu for the growth and replication of EBV. Simi-
larly, they were also determined that prior exposure of EBV
also produced a cellular environment which promotes the
growth and replication of H. pylori. Notably, same stud also
demonstrated that coinfection of H. pylori and EBV pro-
motes the aggressiveness of GC through the upregulation
of oncoprotein Gankyrin and their downstream signaling
molecules (Kashyap etal. 2021).
Conclusion
EBV and H. pylori exist in human systems where they are
known to cause GC independently. Despite this, the coin-
fections are more common in biological systems where the
pathogens interact with each other and enhance the aggres-
siveness of the disease. The coinfection of both microor-
ganisms in GC specimens has been increasingly reported,
suggesting that the interplay between both pathogens may
be implicated in carcinogenesis. Multiple clinical reports
explicitly describe the EBV and H. pylori coexistence in
GC. Moreover, how these pathogens target host factors and
downstream insight into molecular mechanisms is still unex-
plored. Henceforth, uncovering the mechanism of EBV and
H. pylori-mediated aggressive carcinogenesis remains open
for research. The open-ended knowledge regarding the H.
pylori-mediated growth and replication of EBV remains to
be answered. Another point of interest could be the antigens
involved in understanding the progression of GC aggressive-
ness. Critical understanding of why gastric epithelial cells
infected with H. pylori and EBV showing aggressive cancer
properties remains unanswered. Thereby, our review has
given a critical insight into the alteration of multiple signal-
ing pathways in host cells during the infection of both the
pathogens, which can find potential to interlink host–patho-
gen signaling pathways and their effects.
Acknowledgements We gratefully acknowledge theDST-FIST Pro-
ject No. SR/FST/LS-I/2020/621 and Indian Institute of Technology
Indorefor providing facilities and support. This project was supported
by theDepartment of Science and TechnologyDST-EMR project
no.DST-EMR: EMR/2017/001637. We are thankful to CSIR, UGC,
and DBT for fellowship to Dharmendra Kashyap, Pranit Hemant
Bagde, and Vaishali Saini respectively in the form of a research stipend.
We appreciate Ms. Annu Rani, Dr. Tarun Prakash Verma, Samiksha
Rele, Siddharth Singh, Sonali Adhikari, and our other laboratory col-
leagues for insightful discussions and advice.
Author contributions HCJ and DK contributed to the design, data
acquisition, analysis, conceptualization, interpretation, and drafted.
VS, PB and SR contributed to the analysis, interpretation, and drafting.
DC, AKJ and RKP critically revised the manuscript. All authors gave
final approval and agreed to be accountable for all aspects of the work.
Funding This project was supported by the Department of Science
and Technology grant no. DST-EMR: EMR/2017/001637 and Center
for Rural Development and Technology, IIT Indore grant no. IITI/
CRDT/2022-23/05.
Declarations
Conflict of interest The authors declare no conflict of interest associ-
ated with this article.
Ethical approval Not applicable.
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Authors and Aliations
DharmendraKashyap1· SamikshaRele1· PranitHemantBagde1· VaishaliSaini1· DebiChatterjee2·
AjayKumarJain2· RajanKumarPandey3· HemChandraJha1,4
* Hem Chandra Jha
hemcjha@iiti.ac.in
1 Lab No. POD 1B 602, Infection Bio-Engineering
Group, Department ofBiosciences andBiomedical
Engineering, Indian Institute ofTechnology Indore, Indore,
MadhyaPradesh453552, India
2 Choithram Hospital andResearch Center, Indore, MP, India
3 Department ofMedical Biochemistry andBiophysics,
Karolinska Institute, 17177Solna, Sweden
4 Centre forRural Development andTechnology,
Indian Institute ofTechnology Indore,
MadhyaPradesh453552Indore, India