Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_53_библиотеки_им_акад_М_И_Перельмана
.pdf
Gastric malignancies’ symptoms are vague and not specific in general, however,
malaise, loss of appetite, epigastric pain, nausea, and dyspepsia. Later, pronounced
symptoms are associated with an advanced stage that may include weight loss,
significant blood loss, anemia, hematochezia, and hematemesis (Hu et al. 2012).
Cancer reaches body parts such as lymph nodes, liver, lungs, peritoneum, and
metastasis’ symptoms include Sister Mary Joseph sign, a mass around the belly
button, and Troisier’s sign, enlargement of the left supraclavicular node (Zdilla et al.
2019). The most common complications of gastric adenocarcinoma include metas-
tasis to nearby or distant organs and tissues such as lymph nodes, peritoneum, and
liver. Also, the formation of paraneoplastic neurological syndromes, the appearance
of brownish spots all over the skin because of overstimulation of growth factors to
keratinocytes to release tissue factor which then activates the coagulations cascade
(Taketa et al. 2012).
Diagnosis of gastric cancer is essentially made obtaining a biopsy during endos-
copy to visualize the tumor directly. Medical imaging using X-rays with barium
contrast of the upper GI tract to determine if cancer is spread to other body parts to
identify complications like ulcers. Also, abdom inal pelvic CT can be used to
evaluate if the cancer is spread to close by organs or lymph nodes to evaluate the
stage of the tumor. Treatment of gastric cancer depends on the cancer stage; for
initial stages, surgery can be performed to treat cancer; for advanced stages,
treatments include a combination of chemotherapy, surgery, radiation, and targeted
therapy to increase the chance of survival even though palliative surgery can only
relieve the pain. However, the overall survival rate is very low because gastric cancer
is mostly diagnosed at advanced stages.
4.3 Molecular Basis of Gastric Carcinogenesis
Regardless of the nature of the etiological or carcinogenetic factors for gastric
cancer, signal transduction cascades of molecular events take place to enable the
communication between malignant and stromal cells (Machlowska et al. 2018).
Therefore, following distinct pathways and utilizing specific mechanisms of cellular
growth, differentiation, or a program of apoptosis, cell death. The fate of cells will
determine the future of the tumor, whether it will become localized or get
metastasized (Riquelme et al. 2015). Gastric adenocarcinoma development is a
complex process involving multiple genetic alterations. As previously mentioned,
based on tissue pathology, intestinal and diffuse are the two main subtypes of gastric
adenocarcinoma (Ferlay et al. 2010b). Many gastric adenocarcinomas are occasion-
ally occurring in irregular or random instances, with many of those related to genetic,
epigenetic, and environmental risk factors. Many studies have associated environ-
mental and microbial factors to gastric cancer, while others associate molecular
variations with gastric cancer (Pan et al. 2018). For example, chronic microbial
infections such as Helicobacter pylori infection, the causative agent of some types of
peptic ulcers, and Epstein-Barr virus (EBV), the causative agent of mononucleosis,
are reported to predispose the subject to develop gastric cancer (Iizasa et al. 2012).
94 I. A. Malli
https://t.me/medicina_free
As a result of both infections, acute gastritis contributes to an increase in the level of
DNA methylation in the gastric lining. It upregulates cancer cell formation, which
supports diffuse gastric cancer molecular mechanisms, and highlights its develop-
ment (Peleteiro et al. 2012).
The exact mechanism that is responsible for making this type of cancer a more
aggressive phenotype is yet to be uncovered; it may occur sporadically, as a result of
familial factor, or as a hereditary factor; thus, maintaining genomic instability
appears to be a key regulator for gastric cancer (Hudler 2012, 2015). Single-gene
molecular studies suggested that intestinal and diffuse-type gastric cancer evolves
via different genetic pathways (Palli et al. 2010). Some inherited factors are
associated with gastric cancer; however, most of the genetic changes that have
been linked with gastric cancer are acquired (Sereno et al. 2011). Acquired factors
can result from somatic and spontaneous mutations that are generated from gastric
adenocarcinoma and have shown genetic instability in terms of chromosomal insta-
bility (CIN) and microsatellite instability (MSI), which are considered the initial
triggers for gastric carcinogenesis (Maleki and Röcken 2017). Besides the two main
types of genomic instability implicated in the gastric cancer pathophysiology, the
CpG island methylator phenotype (CIMP), which are epigenetic alterations, is linked
with gastric cancer (Puneet et al. 2018).
4.3.1 Hereditary Genetic Factors
The majority of gastric cancer are originating from non-inherited factors; thus, less
than 1–3% of gastric cancer cases are connected to hereditary factors (Sereno et al.
2011). Among these, hereditary diffuse gastric cancer (HDGC) syndrome, an auto-
somal dominant caused by a mutation in the CDH1 gene. This gene encodes
E-cadherin or cadherin-1, an adhesion protein responsible for the tight junction
between epithelial cells and signals transduction to regulate the cell cycle (Paredes
et al. 2012). Mutation in this gene recognizes as a predispositi on syndrome that
increased the risk for the development of gastric cancer, although it is classified as a
rare syndrome (Van Roy 2014). Hereditary diffuse gastric cancer can appear in any
part of the stomach, and it affects both genders equally but is considered more
common in younger generations (Fitzgerald et al. 2010). The mechanism of cancer
cell formation of the hereditary diffuse gastric cancer has been clearly explained and
well-documented. It arises from normal gastric mucosa with no premalignant stage
and characterizes by non-adherent cell formation; adhesion proteins wer e
downregulated to enhance the formation of cancer lesions and spread to adjacent
cells (Assumpção et al. 2020). Thus the loss of function of cadherin-1 will result in
uncontrolled cell division, loss of cellular communication, cellular detachments,
de-differentiation, and metastasis (Piazuelo and Correa 2013). Metastases of cancer
cells from one part to another in the stomach structure, which progresses the disease
rapidly and worsens the condition (Tomita et al. 2011). Also, desmoplasia will be
associated with inflammation and generated as a result of the chronic inflammation,
but with the absence of atrophic gastritis that usually characterizes the intestinal
4 From Inflammation to Cancer: Role of Genetic Polymorphisms of Inflammatory.. . 95
https://t.me/medicina_free
subtype; therefore, this subtype of gastric cancer has a poor prognosis (Bass et al.
2014; Jafferbhoy et al. 2013).
However, the diffuse type has more pronounced desmoplasia, adhesion, and
dense fibrosis with thick and rigid stomach wall caused by the detachment of cancer
cells to invade connective tissue at the submucosa causing GLP (Hanahan and
Weinberg 2011). Mimata et al. have shown evidence that hereditary diffuse gastric
cancer mutation alone is not enough to cause gastric cancer; they proposed multiple
additional factors that are needed to enhance the molecular mechanisms of gastric
cancer pathogenesis (Mimata et al. 2011). Additional mechanisms might also be
involved in the pathogenesis of HDGC, such as CDH1 promoter methylation,
mutations in p53, and missense mutation at c-Met genes (Corso et al. 2011;Ma
et al. 2016). Hereditary gastric cancer is associated with either the polyp type such as
gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), a malig-
nancy of polyps; or the non-polyp type such as hereditary nonpolyposis colon cancer
(HNPCC), which associates with a mutation in DNA repair genes (Carneiro 2012 ).
Also, rare forms of hereditary gastric cancer syndrome, such as Li–Fraumeni
syndrome which is caused by a mutation in STK11 (Masciari et al. 2011; Van Lier
et al. 2010).
4.3.2 Acquired Genetic Factors
Chromosomal Instability Based on the molecular classification of gastric cancer,
chromosomal instability is defined as the accumulation of a high rate of mutations as
a result of structural rearrangeme nts at microsatellite regions of the DNA (Shah et al.
2011). Moreover, gastric cancer risk factors such as alcohol consumption, tobacco
smoking, high salt diet, Helicobacter pylori infection have a great impact on the
chromosomal stability in susceptible individuals (Na and Woo 2014). Infection
induced inflammatory response enhances immune cells’ recruitment such as
lymphocytes, neutrophils, and macrophages. Furthermore, persistent inflammation
is commonly associated with genetic variations and DNA damage that upregulate the
status of chronic gastritis, which is believed to predispose the host to develop gastric
tumorigenesis (Malfertheiner 2011). Gastric cancer is characterized by genetic
instability in terms of permanent DNA damage and DNA repair mechanisms.
Helicobacter pylori infection is believed to generate mitochondrial-DNA mutations,
increase the rate of DNA damage, and decrease DNA repair (Ding et al. 2010).
Spontaneous mutations at the epithelial cells are induced by DNA methylation, and
genomic oxidative instability also differs according to the geographical location,
histological type highlighting the importance of gene–environment interactions in
disease pathogenesis (Sayed et al. 2020). Thus, the two possible mechanisms
suggested the development of chromosomal instability. The first one is the belief
that these mutations are to be because of dysfunction of the DNA mismatch repair
proteins that can occur in both sides of cell cycle regulatory pathways. Tumor
suppressor genes downregulate the cell cycle by coding for proteins that stop the
cell division and promote apoptosis or proto-oncogenes, which upregulate cell
96 I. A. Malli
https://t.me/medicina_free
division and normal code for accelerator proteins that promote the cell cycle
(Machlowska et al. 2018). Because of such mutations, metaplastic cells start divid-
ing uncontrollably, and more mutations are passed with each division to become
malignant cells with special ability to invade nearby cells or metastasize and spread
to distant sites (Cai et al. 2019). The second proposed theory for chromosomal
instability was present of the defected chromosome is within cells that can be carried
to the offspring during mitosis (Duijf and Benezra 2013).
Microsatellite Instability It is reported to be responsible for more than 50% of
sporadic cases of gastric cancers. These causes can be in terms of hypermethylation
of the promoter region known as microsatellite regions due to related epigenetic
changes or mutational inactivation (Velho et al. 2014). These changes cause defects
in DNA mismatch repair (MMR) genes and resul t in the accumulation of mutations
within simple nucleotide repeats by bases insertion or deletion (Li et al. 2020 ).
Inactivation and loss of gene function, which leads to additional genetic changes is
responsible for the development of a higher frequency of gastric cancer (Carcas
2014). Abnormal CpG islands’ promoter hypermethylation is another epigenetic
alteration associated with the transcriptional silencing of human genes reported in
cancers that affect multiple gene promoter regio ns but not a single gene promoter
(Puneet et al. 2018). These epigenetic discrepancies have been recognized in gastric
cancer and known to serve as a mechanism for the silencing of the tumor suppressor
genes and other adhesion protein genes such as E-cadherin (Gigek et al. 2017). It has
been shown that Helicobacter pylori increases the expression of MUC1 by the CpG
hypomethylation pathway, which functions as a signal transducer and activator of
transcription (Puneet et al. 2018).
4.4 Single Nucleotide Polymorphisms and Gastric Cancer
It has been proposed that gastritis during Helicobacter pylori infection generates a
special altered envir onment because of inflammatory cytokines, chemokines, and
growth factors that activate signaling transduction cascade inflammatory events,
which may lead to chronic gastritis. Inflammatory respon se enhances lymphocytes,
neutrophils, and macrophages recruitment (Machado et al. 2010). Furthermore,
persistent inflammation is commonly associated with gen etic variations and DNA
damage that upregulate the status of chronic gastritis, which is believed to predispose
the host to develop gastric tumorigenesis (Malfertheiner 2011). Besides, spontane-
ous mutations at the epithelial cells are induced by DNA methylation, oxidative
damage, chromosomal or microsatellite instability, which downregulate major DNA
repair pathways (Sayed et al. 2020). Single nucleotide polymorphisms (SNPs) are
naturally occurring genetic variations of a single base within the DNA sequence that
occur with variable frequency. Less than 1% of the population carries the same
variation to be considered and classified as an SNP (Huebner et al. 2010). SNPs are
considered one of the most important that stimulate and upregulate the expression
and activity of certain pro-carcinogen genes (Skierucha et al. 2016). The frequency
4 From Inflammation to Cancer: Role of Genetic Polymorphisms of Inflammatory.. . 97
https://t.me/medicina_free
of genetic polymorphisms varies based on ethnicity and affect by environmental
exposure, which promotes the development of gastric cancer (O’Brien et al. 2013).
These variations appear in the genome of different ethnicity as a result of point
mutations, which they regulate and correlate biological pathways, disease suscepti-
bility, drug response, and carcinogenesis (Oh et al. 2020). Alteration of the gene
expression will increase, decrease, or defect the function of its associated protein.
However, not all SNPs are associated with increased risk of diseases; some have no
known pathology while either is protective (Chang et al. 2014). Gastric cancer shows
host genetic variants in terms of SNPs in some genes that induce DNA damage,
impair DNA repair, and decrease the expression of immune response genes (Ding
et al. 2010). Special SNPs within key candidate genes are major factors that
contribute to sporadic cases of gastric cancer (Grabsch and Tan 2013). All of the
sporadic mechanisms end up by alteration and dysregulation of signaling pathways
between host cells and the surrounded environment, which consequently disrupts
mechanisms of the cell cycle, proliferation, and apoptosis (Hanahan and Weinberg
2011).
In terms of the infected host genotypes, presence of SNPs, several genes have
been linked to the host genetic components with the risk of gastric cancer as a result
of infection (Zabaleta 2012). This section aims to investigate SNPs within host genes
involved in the inflammatory response to Helicobacter pylori infection and its
pathological consequences such as gastric atrophy, peptic ulcer, and intestinal type
of gastric cancer (McColl 2010). The risk of developing gastric cancer can be
affected by multiple factors: the presence of a specific strain of Helicobacter pylori
and its virulence factors, the infected host genotypes, and the specific host–microbe
interactions in terms of host inflammator y responses and subtypes of gastric cancer,
which have different epidemiological and pathophysiological features (Peek 2016).
Gastritis is the hallmark of the immune response because of H. pylori infection; it
leads to the induced gastric acid secretion and development of mucosal ulceration,
which consequently leads to gastric atrophy and developing gastric cancer
(Malfertheiner et al. 2014). In an attempt to address the host geneti c variations and
susceptibility associated with SNPs and the risk of developing gastric cancer,
multiple pieces of research have been conducting searching for new polymorphisms
to improve the knowledge about pathogenesis, diagnosis, treatment, and prevention
of gastric cancer at a cellular level (McLean and El-Omar 2014). The following
sections will address possible variations and heterogeneity caused by SNPs, which
represent a spectrum of several key genetic increases, the susceptibility to gastric
cancer, and influences on the pathogenesis of gastric cancer.
4.4.1 Polymorphisms in Cytokine Genes
Cytokines are small molecular weight secretory proteins that are synthesized by
nearly all nucleated cells, such as lymphocytes and monocytes. Their biological
activities inside the host indicated by their roles in response to infection and
98 I. A. Malli
https://t.me/medicina_free
inflammatory utilizing microtubule-associated protein kinase (MAPK) pathway for
initiating their gene expression (Bockerstett and DiPaolo 2017). Upon activation,
cytokines positively and negatively regulate cellular genes expression by binding to
cytokine receptors on the target cells and initiate signal transduction pathways
through the second messenger (Morrison 2012). Many studies have documented
clear associations between cytokines’ genes SNPs that regulate inflammation during
gastric cancer (Hong et al. 2012). Genetic variants in cytokines and cytokines’
receptor genes associated with inflammation are considered to participate in gastric
carcinogenesis initiation and promotion (Persson et al. 2010). Cytokine genes that
are responsible for initiating regulate the production of inflammatory cytokines and
the risk of gastric cancer. Genes of inflammatory cytokines: tumor necrosis factor-
alpha (TNFα), interleukin 1 beta (IL-1 β), interleukin 8 (IL-8), and interleukin
10 genes (IL-10), interleukin 17 gene (IL-17) as well as their coded proteins are
the most studied for their association with gastric cancer (Bornschein et al. 2010;
Peek 2016). These cytokines function as mediators of gastric cancer pathophysiol-
ogy and play important roles in the upregulatin g other risk factors for gastric cancer
(Yuzhalin 2011).
4.4.1.1 Interleukin 1 Gene
For its involvement in upregulating the release of other proinflammatory cytokines
during the early stage of inflammation, interleukin one beta gene (IL-1 β) considers
an ultimate candidate for studying the effects of SNPs and its role during
Helicobacter pylori infection and its association with the development of gastric
cancer (Santarlasci et al. 2013). Chromosome 2q13-14 is the location of IL-1 gene
clusters known to encode three proteins: IL-1RN, IL-1α, and IL-1β, their naturally
occurring receptor antagonist that inhibits their functions (Liu and Cai 2017). Three
polymorphisms have been found in IL-1β and been associated with gastric cancer;
the base transition between C > Tat511 (IL-1β C511T (rs16944)), and base
transition between C > T base transition at +3954 (IL-1β C511T (rs1143634)), and
base transition between T > Cat31 (IL-1β C31T (rs1143627)) (Motamedi Rad
et al. 2018; Zeng et al. 2003). Also, the base transition between A > T at +9589
(IL-1RN A9589T (rs454078)) was reported at receptor antagonist genotype IL-1RN
and has been associated with gastric cancer risk (Bangshun et al. 2011). Since IL-1
plays an important role in inflammation and infection pathogenesis, SNPs in the IL-1
cluster encoding IL-1β and IL-1RN were associated with accelerated risk of devel-
oping gastritis and in response to Helicobacter pylori infection relatives of gastric
cancer cases (Ho ng et al. 2016). IL1β encodes IL-1β, a potent proinflammatory
protein that is released as a proprotein from activated antigen-presenting cells
(APCs) such as macrophages and monocytes during an early stage of acute and
chronic inflammation or infection (Gigek et al. 2017). Once activated, this potent
cytokine accelerates and reinforces the importance of host–environment interactions
by enhancing inflammatory response and upregulating cellular proliferation, differ-
entiation, and apoptosis (Chen et al. 2015). As an endogenous pyrogen, IL-1β
induces prostaglandin synthesis, recruits polymorphonuclear cells (PMNs) such as
neutrophils, activates immune cells, and promotes B-cell proliferation and antibody
4 From Inflammation to Cancer: Role of Genetic Polymorphisms of Inflammatory.. . 99
https://t.me/medicina_free
production (Qian et al. 2010). IL-1β C511T (rs1143634) and IL-1β C31T
(rs1143627) in the promoter regions cause non-random association of alleles at
that loci. IL-1β C31T (rs1143627) regulates transcription factors binding capacity
and there fore affecting the transcriptional activity of IL-1β (Motamedi Rad et al.
2018; Zeng et al. 2003). IL-1RN A9589T (rs454078) polymorphism leads to the
presence of five different alleles of both IL-1RA and IL-1β (Kamenarska et al. 2014).
Proinflammatory genetic polymorphisms tend to contribute to the risk of the
development of gastric cancer, as previously shown by a study, the association of
IL-1β 511C > T (rs16944) with gastric cancer risk (Kamangar et al. 2006). In this
regard, a study conducted by Persson et al. documented that among non-Asian
populations, IL-1β 511C > T (rs16944) and IL-1RN A9589T (rs454078) were
found to be associated and linked to an increased risk of intestinal and diffuse gastric
cancer. While in terms of anatomical location, Persson et al. have investigated the
association between IL1B polymorphisms and gastric cancer at different geographic
locations among Asian and non-Asian participants. Their findings suggested that
there is an increase in gastric cancer risk among non-Asians who carry IL-1β
511C > T (rs16944). Interestingly this risk was accelerated in Helicobacter pylori-
positive cases compared to the control and found to be related more to distal gastric
cancer compared to cardia cancers (Persson et al. 2010).
However, in Asian populations with a high incidence of Helicobacter pylori
infection, IL1B C31T (rs1143627) was mainly associated with a reduced overall
risk of distal and intestinal gastric cancer, while IL-1β C511T (AA;rs16944) carriers
were found to have an increased risk of cardia gastric cancer specifically (Persson
et al. 2010). Moreover, even though IL-1β C511T (rs16944) and IL-1RN A9589T
(rs454078) are considered a positive risk factor for gastric carcinogenesis in certain
populations, they were never associated with the presence of gastric cancer in others
(Baum and Georgiou 2011). In 2012, Kimang’setal
. had conducted a cross-
sectional study among African participants to investigate the effects of
proinflammatory genetic polymorphisms, IL-1β 511C > T (rs16944) and IL-1RN
A9589T (rs454078), and their role in Helicobacter pylori-related gastric cancer
pathology. He reported that both polymorphisms were significantly associated
with gastric pathologies in the presence of Helicobacter pylori infection (Kimang’a
2012). This genetic susceptibility has been validated by Zhao et al. in three different
ethnicities; they reported IL-1β C511T (rs16944) and IL-1RN A9589T (rs454078)
are positively involved with gastric changes and in the development of non-cardia
gastric adenocarcinoma (Zhao et al. 2012). Regardless of the carrier status of
Helicobacter pylori bacteria, gastric cancer was reported with a severe and
prolonged inflammatory response due to increased circulatory levels of IL-1β
C511T (rs16944) and IL-1RN A9589T (rs454078). Most of the literature search
has conclu ded that IL-1β C511T (rs16944) IL-1RN A9589T (rs454078) were related
to increased risk of developing subtypes of gastric cancer, non-cardia, and intestinal
gastric cancer. However, IL1B C31T (rs1143627) was associated with a decreased
risk of distal and intestinal gastric cancer.
100 I. A. Malli
https://t.me/medicina_free
4.4.1.2 Interleukin 8 Gene
For its role as proinflammatory cytokines in upregulating the release of other initial
cytokines during the early stage of inflammation and infection, interleukin 8 (IL-8)
considers a possible candidate for studying the effects of SNPs and its role during
Helicobacter pylori infection and its association with the development of gastric
cancer (Brew et al. 2000). IL-8 belongs to the chemokine subfamily, which is
encoded by IL8 and produced by a variety of tissue and blood cells. Thus, as a
predominantly neutrophil chemoattractant, it attracts and activates neutrophils. High
concentrations of IL-8 have the ability to attract T cell chemokines to induce a
respiratory burst, neutrophils degranulation, and angiogenic activity (Persson et al.
2010). The two receptors of IL-8, IL-8RA (CXCR1) and RB (CXCR2), continu-
ously express with high affinity on the surface of neutrophils, mainly T cells and
monocytes (Brew et al. 2000). Upon Helicobacter pylori infection and colonization,
as a response to inflammation, gastric epithelial cells produce a high concentration of
IL-8 constitutively, and this production is enhanced following cytokine stimulation.
This activation leads to extensive cellular infiltration and enzyme degranulation
(Persson et al. 2010). Upon infection with Helicobacter pylori, CagA induces and
increases IL-8 expression, which is related to the more severe gastritis in the host. An
association between IL-8 promoter polymorphisms and gastric cancer has also been
suggested for some populations (Persson et al. 2010).
There are two functional polymorphisms reported in the promoter region of IL-8:
base transition between at 251 (IL-8251 T/A (rs4073)) and a base transition
between at 845 (IL-8845 T/C (rs2227532)) (de Oliveira et al. 2015). Therefore,
both polymorphisms regulate transcription factors binding to the promoter sites,
which are involved in increased or decreased gene expression. Since they are located
at the promoter regions, they involve in regulating transcription factors affinity to the
promoter site; therefore, they alter expression levels of mRNA and inflammatory
cytokines associated with cancer development (Qadri et al. 2014 ). Several studies
have been conducted to evaluate the influence of IL-8 polymorphisms, IL-8-251 T/A
(rs4073) and IL-8-845 T/C (rs2227532), and the risks of developing chronic gastric
carcinoma. De Oliveira et al. have reported since IL-8 is responsible for tumor-
associated angiogenesis in several cancers, AT heterozygote of IL-8-251 T/A
(rs4073) significantly upregulated and associated with changing in the levels of
IL-8 production (de Oliveira et al. 2015). However, there was no reported associa-
tion between the development of the clinicopathological of gastric cancer and
Helicobacter pylori infection or the presence of IL-8 gene polymorphisms (Taguchi
et al. 2005). In 2011, to understand the relationship between IL-8 polymorphism and
the risk of atrophic gastritis and gastric cancer, Yuzhalin had investigated the host
genetic susceptibility of IL-8 genes and their influence on gastric carcinogenesis
caused by Helicobacter pylori infection. Examining IL-8 -251 T > A in subjects
with atrophic gastritis and with gastric cancer, he reported that level of neutrophil
infiltration and IL-8 production were upregulated by IL-8 -251 A/A genotype, which
was associ ated with a higher risk of gastritis and gastric cancer compared with the
T/T genotype (Yuzhalin 2011). Finally, previous studies provide some evidence that
IL-8-845 T/C has an association with a higher risk of gastric cancer.
4 From Inflammation to Cancer: Role of Genetic Polymorphisms of Inflammatory.. . 101
https://t.me/medicina_free
4.4.1.3 Interleukin 10 Gene
Interleukin 10 (IL-10) is a member of cytokines encoded by IL-10 located at
positions 31 and 32 on the long arm of chrom osome 1, which consists of five
exons and four introns (Yuzhalin 2011). It is produced by B lymphocytes,
macrophages, and T-helper 2 cells, and its activity is directed toward producing
cells and cytokines. IL-10 functions as an anti-inflammatory to limit the production
and minimize the release of proinflammatory cytokines, downregulate inflammation,
inhibit T-helper 1 cell, and upregulate other lymphocytes (Cárdenas et al. 2018).
Multiple polymorphisms were reported to IL-10 in the promoter region, IL10-
A1082G (rs1800896), IL10-592 C > A (rs1800872), IL10-819 C > T (rs1800871)
have been associated with inflammation and gastric cancer (Colt et al. 2009).
Even though many studies have evaluated the association between IL10 -819
C > T (rs1800871) and IL10 -592 C > A (rs1800872) and gastric cancer risk,
findings were inconsistent, and gastric cancer risk was undetermined. J. Liu et al.
explored the role of IL10 -819 C > T (rs1800871) in the susceptibility to gastric
cancer. They concluded that IL10 -819 C > T (rs1800871) is associated with a
reduced risk of gastric cancer among Asians (Liu et al. 2011). Additionally, in the
presence of Helicobacter pylori infection, IL10 -819 C > T (rs1800871) was found
not to be associated with reduced risk of diffuse, non-cardia, or cardia subtype
gastric cancer. Thus, they concluded that IL10 -819 C > T (rs1800871) provides
Asians with some protection against gastric cancer (Liu et al. 2011). Also, Xue et al.
have conducted a meta-analysis trying to figure out these controversies and validate
some previous results. In regard to the association between IL10 -592 C > A
(rs1800872) and gastric cancer risk, they observed that there was a significant
association between IL10 -592 C > A (rs1800872) and gastric cancer risk was
observed in the Asian but not in the Caucasian population. Therefore, he concluded
that the association is ethnicity-specific and cannot be generalized (Xue et al. 2012).
Furthermore, F. Pan et al. performed another meta-analysis to determine the associ-
ation between IL10- A1082G (rs1800896) and the risk of developing gastrointestinal
cancers. They reported a strong link between IL10- A1082G (rs1800896) and
increased risk of gastrointestinal cancers and gastric cancer in the Asian population
(Pan et al. 2012). Kim et al. investigated the associations of developing gastric
cancer in the Korean population with multiple factors such as Helicobacter pylori
infection, tobacco smoking, and IL10 polymorphisms. They reported that in the
presence of Helicobacter pylori and positive smokers, all three polymorphisms:
IL10-592 C > A (rs1800872), IL10- A1082G (rs1800896), and IL10-819 C > T
(rs1800871) were associated with an increased risk of intestinal-type gastric cancer.
Also, Helicobacter pylori infection and smoking have a combined risk to develop
intestinal-type of gastric cancer in the presence of IL10- A1082G (rs1800896) (Kim
et al. 2012).
4.4.1.4 Interleukin 17 Gene
Interleukin-17 (IL-17), a proinflammatory cytokine1, 2, 3 that participates,
contributes to the local and systemic aspects of multiple inflammatory diseases. It
is produced by T-helper 17 cells to participate in the defense against pathogens, such
102 I. A. Malli
https://t.me/medicina_free
as extracellular bacterial, helminthic parasites, and fungal infections (Miossec and
Kolls 2012). However, overexpression of IL-17 might contribute to autoimmunity
and chronic inflammatory diseases such as rheumatoid arthritis (Jin and Dong 2013).
Since chronic inflammation is the hallmark of the pathogenesis of Hel icobacter
pylori infection, proinflammatory cytokines IL-17 and IL-17F are the ultimate
candidate to be studied for their role in Helicobacter pylori-induced gastr ic cancer
(Yu et al. 2012). Numerous studies performed demonstrated that IL-17 stimulates
tumor growth; thus, increase in its expression level might indicate a good prognosis
and survival for cancer cases (Furuya et al. 2018).
Several polymorphisms such as IL-17A G197A (rs2275913) and IL-17F A7488G
(rs763780) have been mapped to IL-17 that encodes proinflammatory cytokines
IL-17 and IL-17F (Bockerstett and DiPaolo 2017). Studies have reported multiple
findings that implicate polymorphisms at IL-17 play a role in regulating the devel-
opment of gastric cancer. Wu et al. had conducted a study utilizing reaction-
restriction fragment length polymorphism to assess the association between
polymorphisms at IL-17 and gastric cancer risk. In 2010, they reported that IL-17F
A7488G (rs763780) and gastric cancer genotypes were associated with an increased
risk of intestinal gastric cancer while IL-17A G197A (rs2275913) was only
associated with an increased risk of poorly differentiated gastric cancer (Wu et al.
2010). Moreover, in 2015, another group had investigated the role of IL-17A G197A
(rs2275913), IL-17F A7488G (rs763780), and IL-17A C > T (rs3748067) in the
development of gastric carcinoma. They reported that during Helicobacter pylori
infection, IL-17A G197A (rs2275913) significantly increased the risk of gastric
cancer (Hou and Yang 2015).
4.4.1.5 Tumor Necrosis Factor-Alpha
Tumor necrosis factor (TNF-α) is a prominent member of the proinflammatory
cytokines family that is recognized as one of the most extensively studied due to
its distinct functions in homeostatic and antimicrobial immunity (Olmos and Lladó
2014). TNF-α is mainly produced by activated APCs such as macrophages, T
lymphocytes, and natural killer (NK) cells (Atzeni and Sarzi-Puttini 2013). TNF-α
plays an essential role in controlling infection as a major neuroinflammatory cyto-
kine that is induced by transcription factors that mediate neuroinflammation via
TNF-α modulation (Muhammad 2019). During Helicobacter pylori infection,
lipopolysaccharide activates proinflammatory cyclooxygenase, which induces by
overexpression of TNF-α. TNF-α gene cluster has multiple polymorphisms that
are linked to the development and increased risk of gastric cancer (Q. Wang et al.
2011). Analyzing TNF-α-308 G/A (rs1800629) and TNF-α-857 C/T (rs1799724)
suggested TNF-α-857 C/T (rs1799724) both associated with a high-risk for devel-
oping gastric cancer in Caucasian populations during Helicobacter pylori infection
(Olmos and Lladó 2014).
4 From Inflammation to Cancer: Role of Genetic Polymorphisms of Inflammatory.. . 103
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана