Abstract:Gastric the strongest risk factor of gastric cancer.

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Last updated: September 19, 2019

Abstract:Gastric cancer (GC) is one of the most common carcinoma and the second leading cause of cancer-related deaths worldwide.

Helicobacter pylori is a gram-negative, microaerophilic gastric bacterial pathogen that is etiologically linked to human gastric cancer. Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor of gastric cancer. The cagA gene-encoded CagA protein is delivered into gastric epithelial cells via bacterial type IV secretion, where it undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs. Infection with Helicobacter pylori cagA-positive strains plays an essential role in the development of gastric carcinoma. CagA shows the ability to affect the expression or function of vital protein in oncogenic or tumor suppressor signaling pathways via several molecular mechanisms, such as direct binding or interaction, phosphorylation of vital signaling proteins and methylation of tumor suppressor genes. CagA continuously dysregulates these signaling pathways and promotes tumorigenesis. In this review I will discuss about how the CagA protein of H.

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pylori is involved in the gastric carcinogenesis, the current knowledge of its molecular mechanism, translocation processes and functions in target cells.Introduction:Gastric cancer being the fifth common malignant and is the third leading cause of cancer related deaths worldwide, with almost 950,000 registered new cases and 700,000 victims each year. (1) The reason behind which is a spiral shaped, gram negative, microaerophilic bacteria Helicobacter pylori, which was discovered by Warren and Marshall in the epithelial lining of the stomach. (2) Although in stomach’s acidic environment no viruses, bacteria or other microorganisms can survive but Helicobacter pylori has evolved uniquely to overcome these barriers.

The majority of H.pylori strains express virulence factors that have evolved to affect host cell signaling pathways.(3) As majority of the population is carrying H.pylori infection along with co-existing chronic inflammation. Mostly H.pylori colonization does not cause any symptoms but it’s long term carriage can increase the risk of development of site specific diseases.

(4)  It is proved through molecular studies that gastric cancer is the cause of combination of both environmental factors and a host genetic component and that accumulation of genetic alteration plays important role in the process of carcinogenesis.(5) There are two major types of gastric cancer. One is the intestinal type gastric cancer which grows slowly, is well-differentiated and does gland formation. While the second is diffused type gastric cancer which is formed of poorly differentiated tumor cells and can be characterized by the mucus production.(6) The increase in the virulence of H.

pylori is due to their ability to produce and secrete a protein called cytotoxin-associated gene A (CagA), encoded by the CagA gene which is one of the ~30 genes present in a 40kb DNA segment that is termed as the cag pathogenicity island (cag PAI) which from an unknown organism was introduced into the H.pylori through horizontal transfer. Many of these cag PAI genes encodes components of syringe like pilus known to be type IV secretion system (TFSS) through which during the bacterial attachment the CagA protein is delivered into the gastric epithelial cells cytoplasm.(7) The infection that causes gastric cancer due to CagA positive strain is more risky than that infection caused with a CagA negative strain.(8) As there are other H.pylori proteins like vacuolating cytotoxin A (VacA) and outer inflammatory protein A (OipA) (9) but the evidence shows that CagA protein plays a central role in gastric carcinogenesis. CagA protein:Cytotoxin-associated gene A (CagA) protein is the virulence factor of Helicobacter pylori.

It is encoded on 40kb cag pathogenicity island PAI. CagA is involved in the development of the gastric cancer. It triggers the host cells and causes conformational changes in the host cell which leads to gastric carcinoma. Through EPIYA-dependent and EPIYA-independent interactions, CagA manifests its pathogenic role. In regulating cell motility and elongation, in intracellular signaling pathways, inflammation mechanisms and disruption of inter-cellular junctions and cellular polarity of gastric epithelial cells.

Since all these pathways are responsible for cellular malignancy, it is said that under persistent H.pylori infection the CagA protein acts as a bacterial oncoprotein. CagA also is a highly antigenic protein and is associated with a prominent inflammatory response thus triggering interleukin-8 production.CagA tridimensional structure and membrane localization:CagA protein is important for host signaling by targeting the epithelial cell membrane and is important for its translocation into host cells.(10) Interaction of CagA-Host cell proteins depends upon localization of CagA into host cell compartments.

This localization is mediated by two membrane domains, the N-terminal and C-terminal domains. The C-terminal domain consists of two regions that are located together in the membrane and interacts with each other when linked to N-terminal domain. The first is phosphotidyl serine binding domain while the second consists of EPIYA and CagA multimerization motifs.(11) For East Asian and Western type of CagA the best model consists of a super helical structure in which N-terminal protrudes at one side while C-terminal has a loop structure. For the C-terminal domain the N-terminal membrane binding domain functions as an inhibitory domain.(10)  Figure 1: Structure of CagA protein for Western type and East-Asian type Translocation of CagA protein of H.pylori to the epithelial cells:CagA being the protein of Helicobacter pylori is encoded by the CagA gene, which is localized by one end of cagA pathogenicity island (cag PAI), a 40kb DNA segment of H.

pylori genome that is considered to be horizontally transferred.(12) The H.pylori strains isolated from the East Asians are almost all CagA positive while the H.pylori strains isolated in western countries do not carry cag PAI an so are cagA negative. Cag PAI:The cag PAI consists of ~30 putative genes in which 18 genes encodes proteins that serves as the building blocks for type IV secretion system.

Which by forming a syringe like structure penetrates into the gastric epithelial cells.(13) Infection due to cagA positive strains of H.pylori associates with severe mucosal inflammation which underlies mucosal inflammation, atrophic gastritis and gastric carcinoma.(14) So now that the attachment of the cagA positive H.pylori occurs to the gastric epithelial cell, the CagA protein of H.

pylori is transferred from the bacterium to the host cells cytoplasm through type IV secretion system.(15) The process is mediated through interaction of CagL with integrins. CagL, also encoded by cag PAI, is then targeted to the surface the pili of type IV secretion system and binds to the host integrins in RGD motif dependent manner.

This interaction of CagL and integrins triggers type IV injection of cagA into the gastric epithelial cells.EPIYA-Dependent CagA-Host Protein Interactions:Once inside the cell, the carboxylic terminal of the cagA serves as a substrate for the tyrosine kinase family Src and becomes tyrosine phosphorylated at sites that contains the EPIYA motifs of 5 aminoacids. There can be variation in numbers and phosphorylation state of these domains which may contribute to the pathogenesis.(16) The C-terminal of CagA protein has a variable number of Glu-Pro-Ile-Tyr-Ala EPIYA motifs that are the site for tyrosine phosphorylation.

Four EPIYA segment have been classified by the amino acid sequence surrounding each EPIYA motif.(17) In East Asian countries the H.pylori strain that circulates is carrying East Asians CagA that consists of EPIYA-A, EPIYA-B and EPIYA-D segments. While in the rest of the world the H.pylori strains carry western CagA that contains EPIYA-A, EPIYA-B and multiple EPIYA-C segments. (18) The CagA upon entering into the host cells undergoes tyrosine phosphorylation on these EPIYA segments, initially by Src family kinases (SFKs) and then c-Abl kinase. The EPIYA-C and EPIYA-D are phosphorylated by SFKs while c-Abl phosphorylates all four EPIYA segments.

The EPIYA-C an EPIYA-D are associated with the highest risk of cancer.(19) Interaction of CagA with SHP-2 oncoprotein:The effects of cagA appears after its phosphorylation, when it interacts with the cytoplasmic protein tyrosine phosphatase SHP-2, Src homology-2 (SH-2) that consists of two domains possessing tandem-repeats at N-terminal region (N-SH2) and another at the C-terminal region (C-SH2). (1) The binding of the two SH-2 domains to the tyrosine-phosphorylated CagA causes a conformational change in the SHP-2. It relieves inhibition of phosphatase domain by the N-SH2 domain which then results in the activation of the SHP-2 phosphatase activity. Here, I will mention again that the East Asian CagA is much active than the Western CagA, as the Western and East Asian CagA species binds SHP-2 through the tyrosine phosphorylated EPIYA-C and EPIYA-D segments.

Here, the activity of EPIYA-D segment binding to SHP-2 is stronger than that of the EPIYA-C segment binding to SHP-2. Due to which the East Asian CagA are more active than Western CagA. (20)There is an important function o SHP-2 in the downstream signal transduction of growth factors or cytokine receptors that promotes morphogenesis, motility and cell proliferation.

After the CagA and SHP-2 interaction, it causes phenotypic change in the epithelial cell that is described as “the humming bird” phenotype. (21) This phenotypic change is characterized by elongated cell shape with dramatic cytoskeleton rearrangements.(12) In the morphogenetic activity of CagA the substrates are dephosphorylated by CagA-activated SHP-2. One such substrate is the focal adhesion kinase (FAK) that has important function in the regulation of focal adhesions which mediates the interaction of cell’s extra cellular matrix.(22) In the gastric epithelial cells the dephosphorylation of CagA-activated SHP-2 occurs at the activating tyrosine phosphorylation sites of FAK which in turns down regulates activity of FAK kinase which is involved in the induction of the humming bird phenotype by CagA.(22) The function of SHP-2 in potentiating the Erk microtubule-associated protein (MAP) kinase pathway by both Ras-dependent and Ras-independent mechanisms, CagA also evokes retained Erk activation, which in the gastric epithelial cells have an important role in the G1 and S-phase of the cell cycle.

(23)CM motif mediated CagA-Host protein interaction:The C-terminal region of CagA protein consists of a 16 amino acid sequence termed as the CagA-multimerization (CM) motif, among the CagA species whose numbers varies. There is a single CM motif in the East Asian CagA that is located proximal to the EPIYA-D segment. While in the western CagA there is also a CM motif after last repeat of the EPIYA-C segment, which is either same to the East Asian CM motif or somewhat related to it.

(17) The 16 amino acid residues of the N-terminal of the EPIYA-C segment are almost identical to the Western CM and almost all Western CagA species consists of two or more CM motifs. CagA dimerization is directed through the sequence of CM motif and it acts as the binding site for polarity regulating serine/threonine kinase, partitioning defective-1 (PAR-1). The kinase activity of PAR-1 is inhibited when CM motif occupies the substrate binding.(24) There are 4 PAR-1 isoforms in mammals where PAR-1b is a predominant member in epithelial cells which binds strongly to the CagA protein. As this PAR-1b forms a homo-dimer in the cell, the resulting dimer interacts with two CagA molecules. That’s why PAR-1 binding sequence was identified as a motif for CagA multimerization.

(25) For increased activity of CagA carrying a single EPIYA-C or EPIYA-D segment this dimerization is quite important. Whereas the interaction of such type of CagA with the two SH2 domains of SHP-2 is weak. Through PAR1-mediated CagA dimerization the a trans interaction of two SH2 domains of SHP2 with CagA proteins occurs which increases the CagA-SHP2 complex stability. Whereas, in cis CagA protein have more than two EPIYA-C segments can associate with a single SHP2 and so the number of EPIYA-C segment in a single CagA protein increases as the CagA-SHP2 complex increases.(25)Figure 2: Major functions of CagA.

CagA translocated into gastric epithelial cells through type IV secretion system where it interacts with signaling molecules that are important for cell regulation, motility and polarity.Role of CagA in Interleukin-8 secretion:The pro inflammatory cytokine secretion that includes production of interleukin 8 (Il-8) production by epithelial cells is stimulated by CagA protein, in vivo. By the delivery of peptidoglycan fragments into host cells, the type IV secretion system may be involved in this complex process, thus enabling the activation of Nod1 that results in induction of Il-8. This induction of Il-8 into gastric epithelial cells is correlated with a functional CagA gene.(26) While in vitro examinations of gastric epithelial cells infected with H.pylori infection, revealed the requirement of cagPAI encoded proteins with exception of CagA, for secretion and regulation of induction of Il-8 by the pathway of NF-kB.

In response to the treatment with CagA-positive and CagA-negative strains, the regulation of Il-8 expression in gastric epithelial cells is reported in response.(27)Conclusion:During the long cohabitation with humans H.pylori has evolved. For the development of gastric cancer in individuals CagA positive strain of the H.pylori acts as a marker. So after the translocation of CagA into the host cell through the gastric epithelial cells, where it causes changes, it promotes the gastric inflammation by inhibition which initiates the multi-stages of gastric carcinogenesis. As compared to the CagA negative strains, the CagA positive strains are more likely to lead the cancer and results in malignancy of the cancer.

While the persons infected with CagA negative strains have a modest but not significant, increase in their risk for cancer.References:1)Masanori HATAKEYAMA(Kumao TOYOSHIMA, M.J.

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