Abstract
The bacterium Helicobacter pylori is linked to the appearance of several gastric diseases and in particular is associated with a progression to gastric cancer. This bacterium colonizes the gastric mucosa directly interacting with epithelial cells. It is well known that H. pylori is associated with alterations in the gastric epithelial cell cycle, and apoptosis, higher levels of mononuclear and neutrophilic infiltrates, more severe atrophy and intestinal metaplasia. In last years, two mechanisms that interact with each other or not have been proposed: the hyperproliferation of gastric cells and oxidative damage of stomach mucosa. In particular, cell cycle alterations induce mitogenic signals and protooncogene expression that may trigger the development of cancer. Contemporary, H. pylori is able to induce polymorphonuclear and mononuclear cells that produce oxygen free radicals that could cause DNA damage to the adjacent cells leading to cancer development. Due to dangerous infection of this bacterium, the scientific community must point out its attention on the development of detection and prevention strategies. Keywords: Helicobacter pylori, cell cycle, inflammation, oxidative stress.

1. Introduction
The Gram-negative bacterium Helicobacter pylori is associated with severe gastric pathologies, including peptic ulcer, chronic active gastritis and gastric cancer. This microorganism is able to invade and colonize human stomach, directly interacting with gastric epithelial cells. Several histological changes are linked with different clinical outcomes, as infiltration of the mucosa (chronic gastritis), loss of mucosal mass (ulcer, atrophy), inflammation trough infiltrating lymphocytes with development of masses (hyperplastic polyps, adenomas, carcinomas, lymphomas). Epidemiological studies have demonstrated an up to 6-fold increased risk of developing adenocarcinoma in patients infected with H. pylori [1,2]. Already in 1994, H. pylori was classified as a type I carcinogen for humans by the IARC/WHO [3]. However, it has been demonstrated that only a subset of H. pylori-infected individuals develop gastroduodenal diseases and gastric cancers because some strains of H. pylori are more pathogenic than others. Several bacterial virulence factors have been described, as well as an urease mediating acid tolerance, adherence factors indispensable for colonization and maintenance of the infection, virulence factors involved in induction of host signalling pathways. H. pylori strains can be divided into two classes, type I and type II, correlated with the presence or the absence of the cag pathogenicity island (PAI), a 40-kb region that encodes over 40 putative bacterial proteins [4,5,6]. Several studies have demonstrated that infection with cagA-positive H. pylori strains is associated with alterations in the gastric epithelial cell cycle and apoptosis, higher levels of mononuclear and neutrophilic infiltrates, more severe atrophy and intestinal metaplasia [7,8,9,10,11]. Moreover, approximately 50% of H. pylori strains express the vacuolating cytotoxin protein VacA [12]. This toxin inserts itself into the epithelial-cell membrane allowing bicarbonate and organic anions release and facilitating the formation of transmembrane pores which permeabilize the gastric epithelium to urea [13,14,15]. Patients with distal gastric cancer frequently present VacA+ strains [16]. A few years ago, another protein HspB [17,18] has been correlated to a major risk to develop a gastric carcinoma [11,19]. This protein is secreted by the bacterium and it has been shown on the mucosa surface and within epithelial cells [20,21,22,23]. Other than the differences between bacterial strains, several factors (environment, diet and host) may influence the risk of developing gastric cancer [24,25,26]. Two principal mechanisms have been proposed for the gastric carcinogenesis induced by Helicobacter pylori: hyperproliferation of gastric epithelial cells and oxidative damage of stomach mucosa. The present review summarizes data about these two different but not opposite systems.

2. Helicobacter pylori interaction with gastric epithelial cells
Helicobacter pylori has adapted to interact specifically with gastric-type epithelial cells. For these reasons, H. pylori infection is limited to areas of the gastrointestinal tract that are lined by gastric epithelium, and the bacterium is known to activate several gastric epithelial cells signalling events [27]. It has been shown that H. pylori is able to induce hyperproliferation of the gastric epithelium [11,28,29,30,31]. The adherence of H. pylori to AGS gastric epithelial cells induces tyrosine phosphorylation of host proteins, cytoskeletal reorganization, NF-kappaB activation, and up-regulation of expression of a variety of inflammatory response genes including IL-8 [32,33,34,35,36]. In addition, H. pylori is able to induce the phosphorylation of MAP kinase family members [11,27]. MAP kinases are a family of ubiquitous, highly conserved, cell signalling molecules that includes three main groups: the extracellular signal-regulated kinases (ERK), the c-Jun N-terminal kinases (JNK), and the p38 MAP kinases [37,38,39]. They can be activated by a wide variety of extracellular stimuli and transmit signals from the cell surface to the nucleus to regulate gene expression. The first and necessary step of MAP kinases activation is the contact between H. pylori and gastric cells [27]. It has been demonstrated that CagA is actively translocated through the type IV secretion system into gastric epithelial cells and then phosphorylated inside the host cell [35,40,41] (Fig. 1). The phosphorylation of CagA is necessary to produce a growth factor-like response of host cells. Interestingly, it has been shown that H. pylori cag+ strains are more potent than cag- strains in inducing MAP kinase activation [27,31]. After this, H. pylori selectively activates ERK pathway driving the phosphorylation of ERK by MEK1/2 that in turn activates this kinase [31]. The activation of ERK leads to phosphorylation of the transcription factor Elk-1, which binds the serum response element motif in the c-fos promoter, thereby inducing c-fos transcription [31,42]. c-Fos, a "master switch" of cell proliferation and differentiation forms together with the phosphorylated form of c-Jun, the transcription factor AP-1 complex [31]. The AP-1 family of transcription factors plays a pivotal role in cell proliferation and neoplastic transformation [43]. Intriguingly, only the strains carrying an intact pathogenicity island are able to induce expression of the proto-oncogene c-fos and phosphorylation of c-Jun and activate the transcription factor AP-1 [31] (Fig. 2). Deregulation of MAP kinase pathway or AP-1 proteins has been shown to induce neoplastic transformation and in this case may contribute to transformation of gastric epithelial cells. An important prerequisite for this malignant transformation is the deregulation of cell cycle. Many pathologies are connected to an altered control of cellular replication. Genes encoding the key-proteins' synthesis for the progression of cell cycle appear modified, deleted or expressed in an abnormal way in cancer cells [11,44]. This is the case of positive regulators such as cyclins and cyclin-dependent kinases or of negative regulators such as the inhibitors of kinases and oncosuppressor genes. Mammalian cyclin-dependent kinases are numerous and each one of them acts in different parts of the cell cycle. These kinases are activated by larger proteins called cyclins, according to their cyclical expression and degradation. The external environment of the cell influences cellular proliferation and differentiation by stimulating and/or inhibiting certain signal transduction pathways. However, each component of the cell cycle machinery, as it relates to cell division, has the potential to elicit or to contribute to a neoplastic phenotype [11,45]. Mitogenic stimulation by growth factors is only effective during G1 phase inducing the transcription of D-type cyclin genes (D1, D2 and D3) [46]. Cyclin D1 expression is up-regulated by ERK1/2 [47] and an AP-1 binding site is present on cyclin D promoter [48,49]. The cyclin D protein concentration is rate-limiting for progression through the G1 phase of cell cycle. Several studies have shown that H. pylori infection induces a transactivation of cyclin D1 transcription in AGS cells leading to an increase of cyclin D1 protein levels [50]. In addition, it has been recently demonstrated that the efficient co-expression of CagA and HspB into AGS cells, is able to influence cell growth by inducing cell cycle proliferation through an increase in the S/G2-M phase of the cell cycle. Moreover, these two bacterial proteins, when transfected in AGS cells, are able to induce an increase of cyclin D3 and Retinoblastoma gene product, in its phosphorylated forms [11,51] (Fig. 2). Over-expression of cyclin D3 has been specifically linked to the progression of several tumors, including pancreatic adenocarcinoma, breast cancer, non-Hodgkin lymphoma and thyroid carcinoma [52,53,54,55]. In particular, it has been proposed that elevated levels of cyclin D3 can titrate p21 and/or p27 away from cyclin D-cdk complexes, leading to an increased kinase activity [52,53]. The phosphorylation of Rb permits the release of the transcription factor E2F1 which, in turn, activates the transcription of genes required for the G1/S passage in the cell cycle [11,56]. Intriguingly, expression of CagA or HspB proteins alone is not able to induce these effects on AGS cells. This may suggest that co-operation among different H. pylori's proteins is necessary to induce cell cycle alterations in the infected cells [11]. All this orderly sequence of events, specifically evoked by H. pylori, induces mitogenic signals and proto-oncogene expression in gastric epithelial cells. The consequent hyperproliferation could trigger the development of cancer.

Figure 1. Infection mechanism of Helicobacter pylori.
The bacterium physically interacts with gastric epithelial cells and introduces CagA protein in host cells.

Figure 2. Interaction between Helicobacter pylori and gastric epithelial cells.
CagA phosphorylation leads to activation of MAP kinase cascade and AP-1 that in turn activate cyclin D/CDK complexes resulting in hyperproliferation of gastric cells.

3. Helicobacter pylori and oxidative stress
It is well known that chronic inflammation of gastrointestinal epithelia unequivocally predisposes to the development of cancers [57]. Patients with enlarged-fold gastritis had an extensive polymorphonuclear and mononuclear cells, particularly macrophages, with H. pylori colonization in their gastric body mucosa. Polymorphonuclear cells and macrophages produce oxygen free radicals that could cause DNA damage to the adjacent cells [58]. Hence, it has been demonstrated that Helicobacter pylori-related gastritis is accompanied by an increased oxygen free radical formation and peroxidative damage [59,60,61,62,63] (Fig. 3). Several authors have reported that free radicals do not provoke oxidative damage in the gastric epithelium directly, but through the formation of peroxinitrite [64], and the levels of nitrotyrosine, a specific marker of peroxinitrite [65], have been reported to be significantly higher in patients with H. pylori positive gastritis than in those with H. pylori negative gastritis [66,67]. Accumulation of oxidative DNA damage could lead to gene modifications of gastric epithelial cells that are mutagenic or carcinogenic [68]. In particular, generation of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) is a cardinal feature of inflammed tissues [69,70]. NO produced by macrophage iNOS has important antimicrobial functions [71,72] and inhibits the growth of different microorganisms that invade the gastrointestinal tract. However, although macrophage-derived NO is important in innate immunity, the high diffusion efficiency of NO makes it potentially reach unintended targets as well as neighbouring epithelial cells [57]. In contrast to macrophage-generated NO, epithelial cell NO has ready access to epithelial cell targets including those important in carcinogenesis. Thus the salutary effect and potentially detrimental consequences of NO generation in inflammation exist along a continuum related to the magnitude and chronicity of NO exposure [57]. Thus, chronic and sustained generation of NO can be associated with direct reactions between NO and cellular costituents and generation of reactive nitrogen species [57]. H. pylori elicits a host inflammatory response with iNOS generation of NO to potentially eradicate the organism. Immunohistochemical analysis has demonstrated the presence of nitrotyrosine with increased iNOS expression in H. pylori gastritis [73]. Because of this bacterium's ability to persist, the inflammatory response become chronic and predisposes to cancer [57,74]. The toxicity of NO during chronic inflammation occurs by two chemical processes: 1) oxidation of NO with superoxide leading to formation of peroxynitrite and nitrosating species; 2) direct reactions between proteins and NO by nitrosylation events [57]. Besides deamination, NO and/or peroxynitrite can cause DNA base oxidation measured as conversion of guanine to 8-nitroguanine and 8-oxoguanine (8-oxodG) [57]. It has been demonstrated that gastric carcinoma patients showed significantly higher levels of 8-hydroxydeoxyguanosine (8-OHdG), the main DNA modifying agent produced by reactive oxygen metabolites (ROMs), in their tumor-adjacent tissues and tumor tissues than in normal tissues [75]. In particular, H. pylori infection is the single most important factor in determining oxidative DNA damage, as assessed as 8-OHdG levels [76]. This molecule may be responsible for DNA base mutation; the adduct can accumulate and is only partially repaired through enzyme pathways that may, in turn, cause further DNA damage [77]. This damage correlates with the onset of precancerous mucosal changes and specifically with atrophy and extensive intestinal metaplasia [76].

Figure 3. Host responses induced by Helicobacter pylori.
The presence of Helicobacter pylori induces the activation of NO pathway in macrophages and gastric epithelial cells resulting in free radical production that induce point mutations and DNA peroxidative damage.

4. From Helicobacter pylori point of view
Although a number of factors have been shown to be essential for colonization and the induction of mucosal damage by Helicobacter pylori [90], little is known about the exact molecular mechanisms that regulate the co-ordinated expression of the genes responsible of these functions [91]. The human stomach is far from a stable habitat, experiencing considerable fluctuations in nutrient availability, reactive oxygen species, pH and temperature, and a certain degree of adaptability would be expected to allow successful and persistent colonization. Given the microenvironment in which the bacterium exerts its effect, it is not surprising that the expression of several H. pylori virulence factors is regulated in response to pH. It is clear that H. pylori is able to sense different environmental stimuli despite the absence of classic global regulators [92,93,94,95,96]. In this scenario, it has been demonstrated that the carbon storage regulator, CsrA, has a unique role in controlling the response to environmental stress and modulating the elaboration of important virulence factors in H. pylori [91]. CsrA is a post-transcriptional regulator that was originally described as a repressor of a variety of stationary phase genes in Escherichia coli [97,98]. CsrA has since been shown to function as a global regulatory protein that represses glycogen synthesis and catabolism, gluconeogenesis and biofilm formation, and activates glycolysis, motility and flagellum biosynthesis [91,97,98,99,100,101]. Moreover, it has been demonstrated that CsrA has a critical role not only in controlling transcript levels of virulence factor genes, but also in mediating acid-induced changes in their expression. In particular, the vacA gene is induced under acidic conditions and this pH-dependent response requires the presence of CsrA [91]. CsrA is crucial for the ongoing survival of H. pylori in the face of exposure to environmental and host-derived stresses and it has been demonstrated that inactivation of csrA significantly attenuates the virulence of a bacterial pathogen [91]. In view to better adapt itself to gastric environment, H. pylori produces a number of detoxifying enzymes that protect it against the effects of oxygen-derived free radicals and have a key role in bacterium ability to survive in the gastric mucosa [91]. For host-generated oxidative stress to reach the pathogen DNA, it needs to overcome several barriers. Some of these are the stomach mucus layer itself, membrane lipids, and bacterial antioxidant enzymes such as superoxide dismutase, catalase and thioredoxin reductase [102,103]. The bacterial antioxidant defenses are not sufficient to avoid oxidative DNA damage generated by a hostile environment leading to mutation in H. pylori genome. Mutagenic lesions reduce the colonization ability of the mutant strain derived by strain with a good colonization capacity [104].

5. Conclusions
Helicobacter pylori chronically infects up to 50% of the world's human population. Its capacity to adapt itself to the host raises from high genetic variability of its genome that reflect a homeostatic mechanism to adaptation to stress situations. The bacterium is able to interplay closely with gastric epithelial cells and to response to diverse environmental stimuli. This association often leads to severe pathologies such as intestinal metaplasia and gastric cancer. H. pylori produces strong variations in host cell cycle determining hyperproliferation and deregulation of important cell mechanism. At the same time, it evokes host responses such as oxidative stress that result more dangerous for the host than for the bacteria since they have been proposed as an alternative mechanism of pathogenesis. In the light of these recent findings, the undiscussed importance of a prevention and a rapid and well performed detection of H. pylori infection are becoming useful tools against the development of severe gastroduodenal diseases.

Acknowledgments
This work was supported by grants from: Cheli Foundation; Malesci SPA; San G. Moscati Hospital, Avellino; Second University of Naples. We also thank I.S.S.C.O. (President H.E. Kaiser) for its continuous support.

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