Helicobacter pylori-induced chronic active gastritis, intestinal metaplasia, and gastric ulcer in Mongolian gerbils

The establishment of persisting Helicobacter pylori infection in laboratory animals has been difficult, but in 1996 Hirayama reported the development of a successful Mongolian gerbil model. The present study was undertaken with two aims: to better characterize the normal histological structure and histochemical properties of the gastric mucosa of the Mongolian gerbil; and to evaluate the progression of the histopathological features of H. pylori-induced gastritis in this animal model for one year after the experimental infection. Seventy-five Mongolian gerbils were used. Mongolian gerbils were sacrificed at 2, 4, 8, 12, 26, 38, and 52 weeks after H. pylori inoculation. Sections prepared from stomachs immediately fixed in Carnoy's solution were stained with hematoxylin and eosin and Alcian blue at pH 2.5/periodic acid-Schiff, a dual staining consisting of the galactose oxidase-cold thionin Schiff reaction and paradoxical Concanavalin A staining, and with immunostaining for H. pylori and BrdU. H. pylori infection induced in the Mongolian gerbil a chronic active gastritis, in which a marked mucosal infiltration of neutrophils on a background of chronic inflammation became detectable 4 weeks after inoculation and continued up to 52 weeks. Intestinal metaplasia and gastric ulcers appeared after 26 weeks in some of the animals, whereas others developed multiple hyperplastic polyps. The Mongolian gerbil represents a novel and useful model for the study of H. pylori-induced chronic active gastritis and may lend itself to the investigation of the epithelial alterations that lead to intestinal metaplasia and gastric neoplasia.     

Comparative analysis of gastric bacterial microbiota in Mongolian gerbils after long-term infection with Helicobacter pylori

Quantitative (qt) real time PCR using 16SrDNA primers is useful for determination of the bacterial composition of the gastric microbiota in Mongolian gerbils. The aim of this study was to determine the change in the gastric microbiota after long-term infection with Helicobacter pylori. One year after inoculation with H. pylori, five gerbils were determined as H. pylori-positive and 6 gerbils H. pylori-negative by culture and real time qt PCR methods. The gastric microbiota of each group of gerbils was also compared with that of 6 gerbils uninfected with H. pylori. DNA from the Atopobium cluster, Bifidobacterium spp., Clostridium coccoides group, Clostridium leptum subgroup, Enterococcus spp. and Lactobacillus spp. were detected in the gastric mucus of both infected and uninfected gerbils. In contrast, Eubacterium cylindroides group and Prevotella spp. were detected only in H. pylori-negative gerbils. The numbers of C. leptum subgroup, C. coccoides group and Bifidobacterium spp. in gastric mucus of H. pylori-negative Mongolian gerbils were significantly lower than those in non-infected gerbils. The results obtained suggest that the composition of gastric indigenous microbiota in Mongolian gerbils may be disturbed by long-term infection with H. pylori, and that these changes may in fact inhibit H. pylori infection.     

Characterization of progressive metaplasia in the gastric corpus mucosa of Mongolian gerbils infected with Helicobacter pylori

Spasmolytic polypeptide‐expressing metaplasia (SPEM) and intestinal metaplasia are considered neoplastic precursors of gastric adenocarcinoma in humans. Loss of parietal cells causes the development of SPEM in the gastric corpus and then chronic inflammation drives SPEM toward a more proliferative lineage. Mongolian gerbils infected with Helicobacter pylori develop chronic gastritis and metaplasia, mimicking aspects of human gastritis with H. pylori infection. We therefore examined metaplastic lineages in the gastric corpus mucosa of gerbils infected by H. pylori strain 7.13, which produces rapid onset of severe inflammation. Six weeks following H. pylori infection, Griffonia simplicifolia lectin II (GSII)‐positive SPEM developed in the base of oxyntic glands in association with parietal cell loss and inflammation. In association with severe inflammation, SPEM glands evolved into aberrant phenotypes, including branched lesions, dilated lesions, and penetrating invasive glands. Mucin 4 (MUC4) was up‐regulated in SPEM and progressive SPEM. Clusterin was expressed in the tips of branched and dilated lesions and throughout regions of invasive glands. Intriguingly, clusterin‐positive regions in these lesions expressed Ki67 and matrix metalloproteinase 7 (MMP‐7). These same regions were also positive for expression of phospho‐IkBα, suggestive of activated NFkB signalling. These findings suggest that clusterin‐positive regions in progressive phenotypes of SPEM have invasive characteristics. Thus, H. pylori infection in gerbils induces SPEM, which then can progress to further aberrant and invasive metaplastic phenotypes. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Emergence of spasmolytic polypeptide-expressing metaplasia in Mongolian gerbils infected with Helicobacter pylori

Spasmolytic polypeptide (TFF2)-expressing metaplasia (SPEM) is observed in mucosa adjacent to human gastric cancer and in fundic glands showing oxyntic atrophy in Helicobacter felis-infected mice. Mongolian gerbils infected with Helicobacter pylori (Hp) develop goblet cell intestinal metaplasia and adenocarcinoma, but the presence of SPEM has not been studied in gerbils. We therefore have sought to examine the development of metaplastic mucosal changes in Hp-infected Mongolian gerbils. Mongolian gerbils were assigned to either uninfected controls or infected with Hp at 17 weeks of age. The animals were killed at 17, 20, 26, 31, 41 and 56 weeks of age. Stomach sections were stained using antibodies for TFF2, intrinsic factor, H/K-ATPase, BrdU and MUC2. Dual immunofluorescence staining for TFF2 with intrinsic factor and for TFF2 with MUC2 was performed. In uninfected animals, no SPEM or intestinal metaplasia was observed. Infected gerbils developed SPEM initially in the intermediate zone along the lesser curvature and subsequently spread out towards the greater curvature. In the earlier stages of infection, SPEM glands demonstrated TFF2 and intrinsic factor double staining cells. However, after 35 weeks of infection, the number of double staining SPEM cells decreased. While early in infection SPEM organized in straight glands, in the later stages of infections, SPEM glands became distorted or dilated along with the development of gastritis cystica profunda that was TFF2 positive. Goblet cell intestinal metaplasia developed only late in the infection. Dual staining for TFF2 and MUC2 showed glands containing both SPEM- and MUC2-positive goblet cell intestinal metaplasia. SPEM develops early in Hp infection in Mongolian gerbils, and alterations in gland morphology arise from SPEM glands during the course of gastric infection with goblet cell intestinal metaplasia developing subsequent to SPEM.     

Serum immunoglobulin G immune response to Helicobacter pylori antigens in Mongolian gerbils

The Mongolian gerbil model for Helicobacter pylori infection is an animal model that mimics human disease. We examined the serum immune response to H. pylori infection in gerbils by enzyme-linked immunosorbent assay (ELISA) and Western blotting, both with whole-cell (H. pylori) extracts. A total of 66 7-week-old specific-pathogen-free male gerbils were inoculated orogastrically with H. pylori strain ATCC 43504. Sera were collected 1, 2, 4, 8, 12, 26, 38, and 52 weeks after H. pylori inoculation. Sixty-nine noninfected gerbils and their sera were used as controls. The specificity of the ELISA was 95.7%. The frequency of seropositivity increased over time: 2 of 10 (20%), 7 of 10 (70%), and 7 of 7 (100%) samples of sera from inoculated gerbils were positive for H. pylori at 2, 4, and 8 weeks postinoculation, respectively. Western blot assays showed that the primary immunoglobulin G (IgG) response against low-molecular-mass (25-, 30-, and 20-kDa) proteins appeared after a lag period of 2 to 8 weeks after inoculation. Antibodies against 160-, 150-, 110-, 120-, 80-, 66-, and 63-kDa proteins were observed 12 weeks after inoculation. The early reactive 30-kDa protein was identified as a urease alpha subunit by N-terminal amino acid sequencing. After 26 weeks, two groups of animals could be distinguished: one group developed ulcers (n = 5), and the other developed hyperplastic polyps without ulcers (n = 19). Gerbils in the gastric ulcer group showed significantly higher serum anti-H. pylori IgG levels than did gerbils in the hyperplastic group (P = 0.001) as measured by ELISA. Furthermore, a higher proportion of animals developed antibodies to H. pylori proteins of 26, 25, and 20 kDa in the ulcer group than those animals with hyperplastic polyps (75 to 100% versus 17 to 50%) in Western blot assays. These results highlight the importance of the immune response of the host in the development of H. pylori-related gastric lesions.     

Colonization and inflammation deficiencies in Mongolian gerbils infected by Helicobacter pylori chemotaxis mutants

Helicobacter pylori causes disease in the human stomach and in mouse and gerbil stomach models. Previous results have shown that motility is critical for H. pylori to colonize mice, gerbils, and other animal models. The role of chemotaxis, however, in colonization and disease is less well understood. Two genes in the H. pylori chemotaxis pathway, cheY and tlpB, which encode the chemotaxis response regulator and a methyl-accepting chemoreceptor, respectively, were disrupted. The cheY mutation was complemented with a wild-type copy of cheY inserted into the chromosomal rdxA gene. The cheY mutant lost chemotaxis but retained motility, while all other strains were motile and chemotactic in vitro. These strains were inoculated into gerbils either alone or in combination with the wild-type strain, and colonization and inflammation were assessed. While the cheY mutant completely failed to colonize gerbil stomachs, the tlpB mutant colonized at levels similar to those of the wild type. With the tlpB mutant, there was a substantial decrease in inflammation in the gerbil stomach compared to that with the wild type. Furthermore, there were differences in the numbers of each immune cell in the tlpB-mutant-infected stomach: the ratio of lymphocytes to neutrophils was about 8 to 1 in the wild type but only about 1 to 1 in the mutant. These results suggest that the TlpB chemoreceptor plays an important role in the inflammatory response while the CheY chemotaxis regulator plays a critical role in initial colonization. Chemotaxis mutants may provide new insights into the steps involved in H. pylori pathogenesis.     

Helicobacter pylori gastritis and primary gastric non-Hodgkin's lymphomas.

AIMS--To evaluate further the relation between gastric malignant lymphoma of the mucosa associated lymphoid tissue (MALT) and Helicobacter pylori. METHODS--One hundred and sixty two surgical specimens of MALT lymphoma were retrospectively investigated to determine tumour type and inflammatory patterns. In 121 cases biopsy specimens obtained before surgery were available and stained with haematoxylin and eosin, periodic acid Schiff, Giemsa and Warthin-Starry stains. RESULTS--Residual lymphoid follicles were found less often in high grade malignant than in low grade malignant MALT lymphomas. Chronic active gastritis was shown within the mucosa at some distance from the tumours in 143 of 146 specimens. In all the cases for which biopsy specimens could be evaluated, colonisation of the mucosa by H pylori had occurred. Lymphoid follicles and lymphoid aggregates were detected in 82.7% of the antral, and in 85% of the body mucosa specimens. CONCLUSIONS--These data support the hypothesis that H pylori has an important role in the development of MALT lymphomas. Furthermore, the chronic inflammation preceding malignant transformation might enhance the probability of malignant transformation via chronic stimulation of the lymphoid tissue. This might in part indicate why MALT lymphomas occur most often in the stomach.     

Helicobacter pylori infection and chronic gastritis in gastric cancer.

AIMS: To investigate the prevalence of Helicobacter pylori associated chronic gastritis in patients with gastric cancer. METHODS: Serum IgG antibodies for H pylori were determined in 54 consecutive patients with gastric carcinoma. The prevalence of H pylori in gastric mucosa was also examined histologically (modified Giemsa) in 32 patients from whom adequate biopsy specimens of the antrum and corpus were available. Thirty five patients with gastrointestinal tumours outside the stomach and 48 with non-gastrointestinal malignancies served as controls. RESULTS: Of the 54 patients, 38 (70%) had H pylori antibodies (IgG) in their serum (three additional patients had H pylori antibodies IgA, class specific but not IgG specific). This prevalence was significantly higher (p less than 0.05) than that (49%) in the 35 controls. No differences in prevalence of H pylori antibodies were found between gastric cancer cases of intestinal (IGCA) or diffuse (DGCA) type, both these types showing H pylori antibodies (IgG) in 71% of the patients. In the subgroup of 32 subjects, five patients had normal gastric mucosa and four showed corpus limited atrophy ("pernicious anaemia type" atrophy of type A). All of these nine patients had no evidence of current or previous H pylori infection in serum (no IgG antibodies) or in tissue sections (negative Giemsa staining). The remaining 23 patients had antral or pangastritis, and all had evidence of current or previous H pylori infection. CONCLUSIONS: H pylori associated chronic gastritis was the associated disease in 75% of the patients with gastric cancer occurring equally often in both IGCA and DGCA groups. About 25% of cases seem to have a normal stomach or severe corpus limited atrophy, neither of which showed evidence of concomitant H pylori infection.     

Up-regulation of cathepsin X in Helicobacter pylori gastritis and gastric cancer

Recently, we identified increased cathepsin X expression in H. pylori-infected gastric mucosa. Here, we describe further up-regulation in gastric cancer and report on the role of inflammatory cytokines required for cathepsin X up-regulation in H. pylori-infected gastric mucosa, as well as on consequences for cellular invasion. Biopsy specimens were taken from the antrum, corpus and cardia of H. pylori-infected and non-infected patients. Gastric cancer samples were obtained from patients undergoing gastric surgery. Cathepsin X was detected in gastric mucosa by quantitative real-time RT-PCR, western blotting and immunohistochemistry. Induction of cathepsin X expression in epithelial and inflammatory cells caused by H. pylori infection was tested in in vitro contact and non-contact co-cultures of AGS cells and monocytic cells. Patients with H. pylori gastritis showed significantly higher cathepsin X mRNA (2.5-fold) and protein (1.6-fold) expression than H. pylori-negative patients. Cathepsin X was also up-regulated in gastric cancer (3-12-fold) compared to non-neoplastic mucosa. Cathepsin X was predominantly expressed by macrophages in the mucosal stroma and in glands of the antral mucosa. In addition, tumour cells stained for cathepsin X in 26 (68%) patients with gastric carcinoma. In general, staining was significantly more common (20 vs. 6 patients) and more intense (3.55 vs. 0.83) in intestinal type gastric cancer than in the diffuse type. In vitro cell culture experiments revealed that intercellular signalling between pathogenicity island (PAI)-positive H. pylori-infected epithelial cells and macrophages via soluble factors in the culture medium seems to be responsible for increased expression of cathepsin X in monocytes. Using antisense oligonucleotides, cathepsin X up-regulation was directly associated with higher invasiveness in vitro. Although no correlation of cathepsin X expression and TNM stage was found, our study demonstrates that cathepsin X plays a role not only in the chronic inflammation of gastric mucosa but also in the tumourigenesis of gastric cancer.     

Effects of Helicobacter pylori infection on the link between regenerating gene expression and serum gastrin levels in Mongolian gerbils

Although regenerating gene (Reg) protein is reported to have a trophic effect on gastric epithelial cells, its involvement in human gastric diseases is not clear. We have recently shown that both gastrin and gastric mucosal inflammation enhance Reg gene expression in the fundic mucosa in rats. This study was designed to clarify whether Reg protein is involved in Helicobacter pylori-induced gastritis and whether Reg gene expression is linked to serum gastrin levels in this condition. Mongolian gerbils were inoculated with an H. pylori strain isolated from a gastric cancer patient. Four weeks later, some of the gerbils with H. pylori infection were eradicated by lansoprazole, amoxicillin, and clarithromycin. The time courses of changes in Reg gene expression, serum gastrin levels, gastric acidity, and histopathologic factors were examined. Four weeks after H. pylori infection, gastritis started spreading to the fundic mucosa, and gastric acidity started reducing. Serum gastrin levels and Reg mRNA expression in the fundus were significantly increased 6 weeks after infection. Reg mRNA expression in the fundus correlated significantly with both serum gastrin levels and the severity of fundic mucosal inflammation. After H. pylori eradication, serum gastrin levels and fundic mucosal inflammation were normalized, and the increase in Reg mRNA expression was abolished. The Reg gene is associated with hypergastrinemia and fundic mucosal inflammation and may be involved in H. pylori-induced gastritis.     

Activation of IkappaB kinase and NF-kappaB is essential for Helicobacter pylori-induced chronic gastritis in Mongolian gerbils

The Mongolian gerbil model of Helicobacter pylori infection resembles human gastritis. In this study, we investigated the role of NF-κB activation in H. pylori-infected gerbils. Activated macrophages were significantly increased in H. pylori-infected gastric mucosa and were identified as being important cells with potent activation of NF-κB, which plays an important part in producing proinflammatory cytokines. Macrophage depletion by the administration of clodronate resulted in milder inflammation in gerbils infected with H. pylori. In macrophages, the inhibition of IκB kinase β (IKKβ), which is a critical kinase for NF-κB activation, resulted in lower proinflammatory cytokine expression caused by heat-killed H. pylori cells. Furthermore, treatment with IKKβ inhibitor resulted in milder inflammation in gerbils with H. pylori gastritis. Collectively, our data suggest that H. pylori-mediated gastric inflammation critically depends on the efficient recruitment and activation of macrophages, with sufficient NF-κB activation.     

Structure of lamina propria lymphoid follicles and associated epithelium in the gastric mucosa during Helicobacter pylori infection in ulcer-bearing Mongolian gerbils

To develop a gerbil model of Helicobacter pylori-induced chronic active gastritis comparable in severity to human lesions, we made acetic acid-induced ulcer in the anterior antral wall and concurrently challenged 1 x 10(8) colony-forming units bacteria per os. At 30 and 60 days after inoculation, the number of viable bacteria colonizing on the surface epithelium of the gastric mucosa was larger in ulcer-bearing animals compared to non-bearing ones. Furthermore, in the former animals, neutrophil and mononuclear cell infiltration as well as lymphoid follicle formation in the lamina propria was more prominent. Electron microscopically, lymphoid follicle-associated epithelium displayed specialized structures. Namely, brush cells interposed between mucous epithelial cells and characterized by prominent microfilament bundles and many apical vesicles or caveola specifically embraced the cluster of intraepithelially invading lymphocytes and macrophage-like cells by the attenuated cytoplasm in an analogous manner to M cells in Peyer's patches. The present study has demonstrated that ulcer formation enhances both H. pylori colonization and lamina propria lymphoid follicle formation and suggested that follicle-associated epithelium might play roles in the delivery of intraluminal antigen.     

Increased gastric epithelial cell proliferation in Helicobacter pylori associated follicular gastritis.

AIMS: An increase in the proliferative state of the gastric epithelium has been attributed to infection with Helicobacter pylori. In order to obtain a more precise estimate of the magnitude of this change, the proliferative state of 17 cases of florid H pylori associated follicular gastritis was examined using the antibody MIB-1. METHODS: Comparable results were produced from control and gastritis cases by using a combination of two reproducible measures of the labelled cells. Dividing cells in the gastric mucosa are concentrated within a proliferating compartment, situated at the base of the crypts. This compartment was measured and expressed as a proportion of the total crypt length. The proportion of positively labelled cells within the compartment was also counted. RESULTS: The proliferation compartment in the gastritis cases occupied 45.6% of the gastric crypt compared with 15.4% in the control group. Of the cells in the proliferating compartment, 79.5% were positively labelled in the gastritis cases and 33.4% in the control group. CONCLUSIONS: The convoluted nature of the gastric crypt does not make it a forgiving experimental model. The use of long lengths of mucosa obtained from gastrectomy specimens permitted the production of consistent results, using a morphometric method. The greater than 100% difference in the proportion of proliferating cells between the two groups suggests that further investigation is warranted.     

Association of Helicobacter pylori with HLA-DR antigen expression in gastritis.

AIMS: To assess the association between Helicobacter pylori-associated gastritis and HLA-DR antigen (class II antigen) expression. METHODS: Fifty endoscopic gastric biopsy specimens were studied for the presence of H pylori, degree and type of inflammation, and for HLA-DR antigen expression in the epithelium. The cases were chosen to represent different categories: inflamed gastric mucosa with (n = 13) and without (n = 20) H pylori, and non-inflamed mucosa (n = 17). RESULTS: The antigen was aberrantly expressed in the antral mucosal epithelium in 11 of 12 cases (92%) with acute-on-chronic gastritis when H pylori was also present. It was present in the antrum in only seven of 18 H pylori negative cases (39%) with acute-on-chronic/chronic gastritis. One of three cases of acute gastritis and three of seven cases of chronic gastric erosions (non-inflamed category) showed positive staining. Generally, there was more staining in the antral than body mucosa and in the surface/foveolar epithelium than in the glands. No aberrant HLA-DR antigen expression was found in the 10 cases of normal gastric mucosa examined. CONCLUSIONS: These findings suggest that H pylori may have a role in the induction of class II HLA antigen expression in chronic gastritis and lend support to the view that these organisms may be responsible for part of the inflammatory response.     

SATB1 expression in gastric mucosa in relation to Helicobacter pylori infection and family history of gastric cancer

PurposeSATB1 protein, the altered levels of which are observed in tumour tissues, acts as a global regulator of gene expression. The aim of the study was to investigate the expression level of the SATB1 gene in gastric mucosa of dyspeptic patients in relation to the H. pylori infection, the family history of gastric cancer (FHGC), and histopathological changes.Material and methodsThe study comprised 64 patients with dyspeptic symptoms. Group I – 28 control patients (10 H. pylori positive) without the FHGC. Group II – 36 patients (16 H. pylori positive) with the FHGC. The samples with normal mucosa (NM) or chronic superficial gastritis (CSG) were used for further analysis. qRT-PCR was used to determine the level of mRNA of SATB1.ResultsThe dominant histopathological changes in group I were NM and CSG. Specimens from group II have demonstrated an increasing frequency of atrophy (A) and intestinal metaplasia (IM). The A and IM specimens have shown increase of expression of the SATB1 and were excluded from further evaluation. In corpus samples of group II patients, the amount of SATB1 mRNA was higher than in antrum samples, regardless of H. pylori infection. The presence of bacterium resulted in the elevated SATB1 expression in corpus samples of group II patients only, while the genetic factor down-regulated SATB1 gene in the antrum samples of the H. pylori negative individuals.ConclusionsThe expression of SATB1 gene correlates with histological changes and is altered by the selected environmental and hereditary factors, and the observed changes may have an impact on the development of gastric cancer.     

幽门螺杆菌诱导蒙古沙鼠胃类癌发生的实验研究

目的 探讨幽门螺杆菌(Hp)感染在蒙古沙鼠胃类癌发生中的作用及Hp去除后对胃类癌发生的影响.方法 100只蒙古沙鼠分成7组,A、B为空白对照组,C、D、E、F、G为Hp感染组,其中F、G组Hp感染后再去除.结果 空白对照组(A、B组)未见ECL细胞增生/异型增生及类癌形成,Hp感染后(C、D、E组),血清抗Hp IgG抗体、胃泌素水平均明显增高(P<0.01),ECL细胞增生/异型增生及类癌发生率分别为27.8%(5/18)、31.2%(5/16)、58.3%(14/24)和16.7%(3/18)、31.2%(5/16)、62.5%(15/24),均明显高于对照组(P<0.01),随着Hp感染时间的延长,ECL病变面积明显增加(P<0.01);Hp去除后,血清抗Hp ISG抗体、胃泌素水平明显降低,ECL细胞增生/异型增生及类癌的发生率降低,分别为25.0%(4/16)、15.4%(2/13)和37.5%(6/16)、23.1%(3/13).早期阶段去除Hp(G组),ECL病变发生率及类癌的面积明显低于非去除组(E组)(P<0.001).血清抗Hp ISG抗体与胃泌素水平及胃泌素水平与胃类癌的发生呈正相关(P<0.001).结论 Hp感染在蒙古沙鼠胃类癌发生中起重要作用,去除Hp可有效预防蒙古沙鼠胃类癌的发生.     

幽门螺杆菌感染与胃黏膜增殖及与胃癌预后的关系

目的 :探讨增殖细胞核抗原 (PCNA)在幽门螺杆菌 (HP)感染的不同胃黏膜增殖性病变演进中的表达情况及其相互关系 ,并着重探讨HP感染对胃癌预后的意义。方法 :对 14 5例经病理证实的不同胃黏膜病变用免疫组化方法检测PCNA标记指数 (LI) ,Warthin Starry(W S)法检测HP感染。结果 :在浅表性胃炎 (CSG)、萎缩肠化性胃炎 (CAG +IM)、异型增生 (DYS)、早期胃癌和进展期胃癌中 ,PCNA LI为 2 4 0 0± 17 88,4 6 5 9± 18 15 ,6 0 5 9± 2 0 2 6 ,5 7 92± 15 15 ,71 0 8± 2 1 2 5。在IM、DYS、胃癌组织均高于CSG(P <0 0 5 )。PCNA阳性表达与胃癌组织类型、浆膜浸润和淋巴结转移密切相关 ,而且Bor rmannIV高于早期胃癌 (P <0 0 5 )。PCNA阳性表达与肠型胃癌HP感染有关。CAG +IM、DYS和GC组PCNA阳性表达中HP感染者高于阴性者。胃癌HP阳性者 5年存期短于HP阴性者。结论 :PCNA基因表达与胃黏膜增殖和恶化有关。HP感染和胃黏膜增殖和恶化有关 ,HP感染与胃癌预后有关。