Gastric cancer is one of the leading causes of cancer death worldwide. It is a heterogeneous cancer that has been useful for studying carcinogenesis and tumorigenesis. One idea discussed is how the bacterial pathogen H. pylori and the inflammatory cytokine IL-1α cooperate to promote α-catenin translocation, which is associated with epithelial-to-mesenchymal transition (EMT). Another idea is that the inflammatory microenvironment contributes to EMT in gastric cancer by altering cancer cells, potentially through specific immune cells. A third idea is that infection with H. pylori induces EMT markers and the emergence of cancer stem cell-like properties in gastric cells, and eradicating H. pylori reduces these

1. Ideas in Gastric Cancer Research
By: Samieh Asadian
Ph.D candidate of Molecular medicine
School of Medicine, QUMS
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2. 2

3.  Gastric cancer isoneof the
leading causesof cancer death
worldwide.
 Becauseof itsheterogeneity,
gastric cancer hasbeen an
interesting model for studying
carcinogenesisand tumorigenesis.
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4. Idea#1: Currently, it is not clearif there is an association
between CagA and IL-1𝛽at a cellularlevel.
 Chronic inflammation. isan important driver of different typesof cancer.
 Particularly, GC evolvesthrough progressiveinflammatory lesions, starting with
superficial gastritis, followed by atrophic gastritis, intestinal metaplasia, and
dysplasia, to finally becomeacancerouslesion.
 Precancerousgastric lesionsarecharacterized by prominent infiltration of
mononuclear and polymorphonuclear immunecellsand thepresenceof
inflammatory cytokines, such astumor necrosisfactor 𝛼(TNF𝛼), interleukin- (IL-)
1𝛼, and IL-8.
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5.  Epidemiological data also support an association
between GC and polymorphismsin thegenes
encoding TNF𝛼, IL-1𝛼, and IL-8.
 By analyzing theeffectsof IL-1𝛼and CagA on
MCF-10A nontransformed cells.Researcher found
evidencethat both CagA and IL-1𝛼trigger the
initiation of theepithelial-to-mesenchymal
transition characterized by 𝛼-catenin nuclear
translocation, increased expression of Snail1 and
ZEB1, downregulation of CDH1, and
morphological changesduringMCF-10A acini
formation.
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6.  only CagA induced MMP9 activity and cell invasion.
 Somedatasupport that IL-1𝛼and CagA target the 𝛼-catenin pathway, with CagA
leading to acquisition of astagerelated to aggressivetumors.
# Idea: how CagA aloneand/or cooperating with theinflammatory cytokineIL-1𝛼
promotes 𝛼-catenin translocation?
# Is there any evidencethat thecombination of thetwo stimuli wasableto
inducethetranslocation of 𝛼-catenin into thenuclei of cellswith an additiveor
synergistic effect?
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7. # When 𝛼-catenin and E-cadherin wereanalyzed by Western blot, researcher
observed that both proteinsremain stableafter both CagA and IL-1𝛼stimuli
at early experimental timepoints. And then E-cad protein decreased # is it
because of lessexpression or moredegradation?
 ZO-1, E-cadherin, and 𝛽-catenin are part of the epithelial apical
junctional complexes that regulate cell polarity, proliferation, and
differentiation.
# study on ZO-1 expression in Gastric Cancer.
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8.  In AGSand MKN74 cellsH. pylori
induced expression of mesenchymal
markersZEB1, vimentin, Snail1, Snail3,
and MMP9 with concomitant decreasing of
theepithelial marker keratin-7.
 EMT also generated cellswith
characteristicsof cancer stem cells(CSC)
and expression of CD44.
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9. Idea#2: Inflammatory microenvironment contributes to
epithelial-mesenchymal transition in gastric cancer
 how theinflammatory environment affectsGC initiation and metastasisviaEMT?
 Another key factor leading to approximately 10% of GC casesisEpstein-Barr virus
(EBV) infection.
 studies on the role of EBV are still in their infancy.
# Although the relationship between H. pylori or EBV and the
prognosis of GC patients is unclear.
 theseinfectionscan inducephysiological and morphological changeswithin the
gastric epithelium, resulting in an increased risk of neoplastic transformationssuch
ashypochlorhydria and gastric atrophy, which areprecursorsof GC.
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11. Immune cells and EMT
 Themajor infiltrating functional immunecellsin GC are T cells, macrophages, NK
cells, DCsand MDSCs.
 in the gastric cancer microenvironment,the aberrant secretion by immune
cells might lead to dysfunction and also stimulate GC cells to become
resistant. In this way, GC cells are likely to gain the ability to continuously
proliferate, become protected from apoptosis and escape immune
surveillance.
#which immunecellsalter GC cellsundergoing theEMT in theinflammatory
microenvironment ?
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12. Idea #3: Eradication
of H.pylori reduced the expression of TGF-β1, Twist, Snail, Slug and vimentin
mRNA as well as the
immunohistochemical expression of CD44
 Interestingly, recent studieshavesuggested that cellsundergoing theEMT acquire
stem cell-likeproperties.
• induction of EMT in immortalized mammary epithelial cellsgenerated a
subpopulation of CD44+/ CD24− cellswith both thephenotypeand propertiesof
breast CSCs. Considering theevidenceindicating EMT and astem cell asan
origin of breast cancer.
• it isof interest to investigatewhether H.pylo ri isacommon triggering factor for
both EMT and CSCsin gastric cancer. Transforming growth factor-β (TGF-β) is
known to bepotent inducer of EMT.
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13. # the influence of H.pylo ri infection and itseradication on EMT or theemergence
of CSCshasnot been investigated to date.
• Twist expression associated with theepithelial-mesenchymal transition in
gastric cancer.
• # The positive mRNA expression rate of Twist and Vimentin in the
cancertissues of patients with lymph node metastasis was significantly
higherthan those in patients without lymph node metastasis.
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14.  ThepositivemRNA expression rateof Twist and
Vimentin wasalso higher in gastric cancer tissues
with lower differentiation gradeand greater
invasion area.
 ThepositivemRNA expression rateof Twist and
Vimentin in cancer tissuesfrom early-stage(I, II)
cancer patientswassignificantly lower than that
in advanced-stage. # Is it good candidate
for biomarker of advanced stageof
Gastric cancer? 14

15. Idea #4:
DARPP-32: a link between infection and gastric cancer
 Researchershaveuncovered a novel pathway underlying theoncogenic
effectsof Helicobacter pylori infection in gastric cancer.
 Thenew findingsshow that H. pylo ri infection activatesthepro-inflammatory
transcription factor NF-κB, which in turn activatestheoncogeneDARPP-32 (also
known asPPP1R1B), promoting cell survival.
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16.  H. pylori infection inducescell death and DNA
damagein the gastric epithelium. However, the
development of apoptosis-resistant cellswith
damaged DNA enhancestherisk of
tumorigenesis. Themechanismsunderlying this
processareunclear.
 previously reported overexpression of DARPP-
32 in about two-thirdsof human gastric cancers.
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17.  Importantly, H. pylori-induced DARPP-32 expression wasassociated with
increased cell survival and activation of thepro-survival AKT pathway in the
gastric cancer cell line.
 DARPP-32 isan important bridgebetween inflammation and cell survival .
 Thefuturedevelopment of potential inhibitorsagainst DARPP-32 might beanovel
strategy for treatment of gastric cancer .
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18.  Amplification and overexpression of DARPP-32 in gastric cancer promote
activation of several oncogenic signalling pathwaysand resistanceto anticancer
drugs.
 NF-κB-p65 bindsto and activatesDARPP-32 promoter and transcription.
 H. pylori-mediated activation of NF-κB transcriptionally regulatesDARPP-32
expression to counteract cell death and promotecell survival.
 Given theDARPP-32 prosurvival oncogenic functions, upregulation of DARPP-
32 could bea key component of H. pylori-mediated gastric tumourigenesis.
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19.  Recent study strongly suggests that inflammation-regulated DARPP-32
constitutesakey component of H. pylori-mediated gastric tumourigenesis.
 How might it impact on clinical practicein theforeseeable
future?
 The study provides a novel understanding of mechanisms by which H.
pylori infection promotes cell survival and the development of gastric
cancer.
 H. pylori–NF-κB–DARPP-32 axis provides a new paradigm in gastric
carcinogenesis that explains the link between infection, inflammation
and gastric carcinogenesis.
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20.  Development of potential inhibitors against DARPP-32 might be
of clinical value in gastric cancer.
 Given the high frequency of DARPP-32 overexpression and its
prosurvival oncogenic functions, the induction of DARPP-32
expression following H. pylori infection and activation of NF-κB
provides a link between infection, inflammation and gastric
tumourigenesis.
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21. References
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