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Role of polymorphisms in genes that encode cytokines and Helicobacter pylori virulence factors in gastric carcinogenesis

The Helicobacter pylori (H. pylori) infection is a determinant factor in gastric cancer (GC) development. However, the infection outcomes are variable and depend on both host and bacterial characteristics. Some host cytokines such as interleukin (IL)-1β, IL-1Ra, IL-8, IL-10 and tumor necrosis factor-α play important roles in the host immune system response to the pathogen, in the development of gastric mucosal lesions and in cell malignant transformation. Therefore, these host factors are crucial in neoplastic processes. Certain polymorphisms in genes that encode these cytokines have been associated with an increased risk of GC. On the other hand, various virulence factors found in distinct H. pylori bacterial strains, including cytotoxin-associated antigen A, vacuolating cytotoxin, duodenal ulcer promoting gene A protein, outer inflammatory protein and blood group antigen binding adhesin, have been associated with the pathogenesis of different gastric diseases. The virulent factors mentioned above allow the successful infection by the bacterium and play crucial roles in gastric mucosa lesions, including malignant transformation. Moreover, the role of host polymorphisms and bacterial virulence factors in gastric carcinogenesis seems to vary among different countries and populations. The identification of host and bacterium factors that are associated with an increased risk of GC development may be useful in determining the prognosis of infection in patients, what could help in clinical decision-making and in providing of an optimized clinical approach.

Core tip: Various polymorphisms in host genes that encode cytokines and Helicobacter pylori virulence factors have been associated with different tendencies of gastric diseases development. Several reviews have been written on the role of host and bacterial isolated factors in gastric carcinogenesis. However, only a small amount of reviews unites the important characteristics of both bacterium and host in carcinogenesis. General overviews about polymorphisms in genes that encode cytokines are also scarce. We aimed to join the main polymorphisms in genes that encode cytokines and bacterial virulent factors related to gastric carcinogenesis and to provide a broad overview about these themes.

INTRODUCTION
Helicobacter pylori (H. pylori) is a gram negative bacterium, which inhabits the gastric epithelial tissue of most people in the world [1] , and it is considered a determinant factor in the initiation of gastric carcino genesis [2] . Gastric cancer (GC) is one of the four most prevalent neoplasms and the second biggest cause of deaths in consequence of cancer worldwide [3] . Despite the importance of H. pylori in gastric carcinogenesis, the development of GC only occurs in a minority of infected people, demonstrating that the infection outcomes are variable. It is believed that multifactorial precancerous processes associated with both host mucosal infla mmatory response and pathogen characteristics are determinant in the severity of the disease [4] . The host immune system response plays a crucial role in the outcomes of H. pylori infection. Polymor phisms in genes that encode cytokines have been reported and associated with the severity of gastric mucosa inflammation and GC development. Some of these determinant variations are present in genes that encode cytokines such as interleukin (IL)1β, IL1Ra, IL8, IL10 and tumor necrosis factor (TNF)α [513] . These polymorphisms are important aspects in understand ing gastric carcinogenesis, since chronic inflammation induced by the bacterium is critical in the emergence and evolution of GC precursor lesions ( Figure 1) [14] .
On the other hand, the virulence factors of H. pylori are determinant in the interaction with host cells. Cytotoxin associated antigen A (CagA), vacuolating cytotoxin (VacA), duodenal ulcer promoting gene A protein (DupA), outer inflammatory protein (OipA) and blood group antigen binding adhesin (BabA) are de Brito BB et al . Polymorphisms and virulence factors in carcinogenesis some virulent factors that seem to be associated with different risks of GC development [15] . Furthermore, H. pylori with EPIYAD or more than one EPIYAC segment in its CagA gene have been associated with a higher risk of gastric carcinogenesis [1620] .

CARCINOGENESIS
Gastric carcinogenesis is a process in which chronic inflammatory status plays a crucial role. The increase of inflammatory cytokine levels, due to H. pylori in fection, seems to be determinant in the initiation and progression of GC [12] . The intensity of the expression of cytokines can be modified by functional polymorphisms in the promoter regions of the genes, which has the potential to alter the affinity of transcription factors, interfering in the expression levels of the messenger ribonucleic acid (mRNA) of specific inflammatory media tors related to the susceptibility of GC initiation [21] .

IL-1
IL1 is a family of cytokines that possesses 11 descri bed members, among which IL1β and IL1 receptor antagonist (IL1Ra), combined with H. pylori infection, seem to be key factors in GC development [2224] . Sig naling through the IL1 receptor is a necessary event for the beginning and sustenance of various responses of the immune system [25] . The promoter regions of IL1B and IL1RN genes, which encode IL1β and IL1Ra respectively, have SNPs that modify the expression of the genes and affect the inflammatory response [26] . These SNPs increase the IL 1β/IL1Ra ratio, which unleashes processes that result in gastric hypochlorhydria, favoring GC development [15,27] . IL1β is an important cytokine for hostresponse to pathogens; however, this mediator can exacerbate damage during chronic diseases [28] . High levels of IL1β in H. pylori infections lead to gastrin overexpression, increased gastric inflammation, hypochlorhydria, and gastric atrophy [29] . Moreover, IL1β might promote neoplastic growth [30] . The IL1B gene can be compos ed by three different SNPs: CT base transition at IL 1B511 (rs16944), TC base transition at IL1B31 (rs1143627) and IL1B3954 (rs1143634), and all of them are strongly associated with increased production of proinflammatory cytokines, hypochlorhydria and increased GC risk, mainly intestinal type, among Cau casians, but not among Asians or Hispanics [3134] . IL1Ra inhibits IL1α and IL1β by means of binding to IL1 receptors. IL1RN possesses a changeable number of tandem repeats in intron 2, forming long alleles (IL1RN1) with 36 repeats or a short allele (IL1RN2) with 2 repeats [35] . The IL1RN2 allele is ass ociated with severe gastric lesions and higher risk for GC, besides raised IL1β expression in Caucasians [3336] . September 14, 2018|Volume 9|Issue 5|

IL-8
IL8 is a potent cytokine that induces the directed migration of cells to inflammatory sites, acting as a chemoattractant [37] . IL8 secretion can be increased by different stimuli, such as live bacteria (including H. pylori) and lipopolysaccharides (LPS), besides others inflammatory cytokines, including IL1 and TNF [38] . The association of IL8 with angiogenesis, adhesion and tumorigenesis have been related [39,40] . The gene CXCL8, which encodes IL8, is located on 4q1221 chromosome and possesses four exons and three introns [41] . An A/T SNP in the 251 position of this gene (rs2227532) has been associated with the development of various inflammatory diseases and cancer, including GC in Asians, but not in Europeans [42,43] . Furthermore, the IL8251 A allele was related to increa sed levels of IL8 [41] .

IL-10
In opposition to the cytokines mentioned above, IL10 is an antiinflammatory cytokine, and it is involved in the cytotoxic response of inflammation and in cell downregulation. Moreover, this mediator prevents the production of proinflammatory cytokines, including TNFα and IL8 [44] . Some studies have demonstrated that SNPs, particularly IL10592 (rs1800872) and IL101082 (rs3021097) alleles, might modulate trans criptional activation and affect IL10 production in vitro. These IL10 polymorphisms are related to lower mRNA expression of this cytokine and it have been associated with GC development in Asians [4548] .

TNF-α
TNFα composes the TNF/TNFR cytokine superfamily and it is involved in maintenance and homeostasis of the immune system and host defense [49] . However, this cytokine is related to various pathologic processes, including autoimmunity, chronic inflammatory processes and malignant disease [50] . According to studies, TNFα signaling through TNFR1 (TNFα receptor) is important for gastric tumor development [51,52] . Some SNPs in the TNFα gene are related to in creased expression of this cytokine. Among these polymorphisms, TNFα857 C/T (rs1799724), TNF α308 G/A (rs1800629) and TNFα238 G/A (rs361525) are the most studied ones. TNFα308 G/A was significantly associated with GC only in Caucasians, while TNFα857 and TNFα238 were related to an increased risk of gastric tumorigenesis in Asians, but not in Caucasians [5355] .

H. PYLORI VIRULENCE FACTORS AND CARCINOGENESIS
The capacity of H. pylori bacteria to trigger a car cinogenic process is not limited to the intense immune response that they unleash, but it also depends on various bacterial factors that can start and modulate neoplastic processes [56] . Different virulent factors found in distinct bacterial strains have been closely associated with the emergence of gastric carcinogenesis. However, genetic variations in genes that encode these virulence factors as well as geographic differences can influence the role of these proteins in GC emergence [15] .

CagA
CagA is encoded by the cagA gene, present in a DNA   [57] . Various cag PAI genes are involved in the codification of elements of a pilus structure named type Ⅳ secretion system (TFSS), which has the function of transporting CagA from bacterium to the cytoplasm of the cells from gastric epithelium [58] .
After being injected into host cells by TFSS, CagA suffers tyrosine phosphorylation at a carboxiterminal segment compound by distinct number of EPIYA (Glu ProIleTyrAla) regions. There are different EPIYA segments A, B, C and D, which contain distinct amino acids in their structure [20] . EPIYA A and B segments are present in most CagA proteins and are followed either by 03 EPIYAC segments in H. pylori strains from Occidental countries or by EPIYAD segments in Eastern countries [59] . Following EPIYAC or EPIYAD phosphorylation, an interaction between these segments and SHP2 possessing SH2 domain occurs, unleashing SHP2/ mitogenactivated protein kinases (MAPK), ERK1, 2JAK and STAT3 pathways [20] . Cytotoxin associated antigen containing EPIYAD or more than one EPIYAC segment ties to SHP2 more strongly, being more effective in the activation of the pathways mentioned above [60] . This process, activated by CagA, leads to dysfunction of cell growth and of celltocell contact inhibition, cell migration, epithelial cell elongation, and increase of epithelial cell turnover, increasing the propensity of acquirement of precancerous genetic changes by damaged cells [61] . Furthermore, it was demonstrated that relatives of GC patients are more often infected by H. pylori strains with more than one EPIYAC segment in CagA structure [62] . Another study carried out by this same group, performed in a Brazilian population, showed that the host signal transducer and activator of transcription protein 3 (STAT3) rs7744166 polymorphism, as well as being infected by H. pylori with CagA containing more than one EPIYAC segment, are independent predisposing factors for GC [20] .

VacA
VacA is another determinant virulence factor in H. pylori infection and in gastric carcinogenesis. Patients infected with VacApositive H. pylori strains have a higher propensity for GC development when compared with patients colonized by VacAnegative strains, either in American or in Asian people [63] . Particularly, individuals infected with H. pylori strains VacA s1, m1 and s1m1 had an increased risk for gastric carcinoge nic unleash in Middle East, Africa and Latin America populations [64] . The peptide mentioned above has only two functional domains in its structure. One of them, the p5558 domain, has the function of binding to rece ptors of gastric epithelial cells. The other functional domain, p3337, produces the cytotoxic effect [65] .
VacA is a 90 kDa exotoxin that is activated in a low pH environment [66] . This toxin promotes the generation of numerous acidic vacuoles in gastric epithelial cell cytoplasm [67] . In this process, VacA affects the structure and function of the membrane, the endoplasmic reticulum, the Golgi apparatus and the mitochondria, which can lead to cell death. Furthermore, vacuolating cytotoxin also plays an important role in the activation and suppression of the immune response [68] . This peptide induces a powerful inhibition over T lymphocyte proliferation by means of an interaction with dendri tic cells, which are reprogrammed to a tolerogenic genotype [69] . The damage and the immunomodulation performed by this toxin contributes to the increase of gastric mucosa inflammation, ulceration and car cinogenesis in mammals [68] .

DupA
Unlike the other virulence factors mentioned in this article, DupA seems to be a protective condition for GC. The dupA gene is constituted by two homologue genes of virB4, jhp0917 and jhp091, which constitute a continuous gene. The real function of the protein encoded by dupA is still obscure, however, its mech anisms seems to be related to the increase of the production of IL8 in the gastric antrum, contributing to the development of gastritis that predominates in that gastric region, a process that leads to duodenal ulcer formation [70] . DupA has been significantly associated with duodenal ulcer formation in Asian countries, but this relation was not observed in the Western population [71] . Furthermore, DupApositive H. pylori has been asso ciated with eradication failure [72] .

OipA
OipA constitutes a group of peptides described as outer membrane proteins (OMPs), a H. pylori protein family composed of 32 components [73] . OipA has been described as a better marker for severe clinical outcomes than CagA, since the infection by strains possessing OipA is an independent determinant risk factor of GC vs gastritis in Americans [74,75] . OipA enhances IL8 production and leads to an increased inflammation status of gastric epithelium. Moreover, it was observed that OipA could inhibit the maturation of dendritic cells in vitro, which might contribute to the immunomodulatory processes performed by H. pylori [76] . BabA babA is a gene that encodes an adhesin whom allows the specific binding to the b and H1 Lewis antigens, which are expressed in the surface of the gastric mucosa cells [77] . The adhesion of the H. pylori to the gastric epithelium mediated by blood group antigen binding adhesin (BabA) appears to play a critical function in the transference of bacterial virulence factors to the host cells. This process contributes to the development of tissue lesions, and a high correlation of babApositive strains of H. pylori with GC has been described [78,79] .

CONCLUSION
Despite the wide knowledge about host and H. pylori interaction developed since the discovery of its colonization in human stomach, many characteristics that contribute to the infection outcomes are still ob scure. The understandings about host polymorphisms in genes that encode cytokines and bacterium virulence factors in GC development are important not only for the determination of patients' prognosis, but it is also a potential way for the development of new preventive and therapeutic strategies.