Helicobacter pylori,gastric microbiota and gastric cancer relationship: Unrolling the tangle

Helicobacter pylori infection (Hp-I) represents a typical microbial agent intervening in the complex mechanisms of gastric homeostasis by disturbing the balance between the host gastric microbiota and mucosa-related factors, leading to inflammatory changes, dysbiosis and eventually gastric cancer. The normal gastric microbiota shows diversity, with Proteobacteria [Helicobacter pylori (H. pylori) belongs to this family], Firmicutes, Actinobacteria, Bacteroides and Fusobacteria being the most abundant phyla. Most studies indicate that H. pylori has inhibitory effects on the colonization of other bacteria, harboring a lower diversity of them in the stomach. When comparing the healthy with the diseased stomach, there is a change in the composition of the gastric microbiome with increasing abundance of H. pylori (where present) in the gastritis stage, while as the gastric carcinogenesis cascade progresses to gastric cancer, the oral and intestinal-type pathogenic microbial strains predominate. Hp-I creates a premalignant environment of atrophy and intestinal metaplasia and the subsequent alteration in gastric microbiota seems to play a crucial role in gastric tumorigenesis itself. Successful H. pylori eradication is suggested to restore gastric microbiota, at least in primary stages. It is more than clear that Hp-I, gastric microbiota and gastric cancer constitute a challenging tangle and the strong interaction between them makes it difficult to unroll. Future studies are considered of crucial importance to test the complex interaction on the modulation of the gastric microbiota by H. pylori as well as on the relationships between the gastric microbiota and gastric carcinogenesis.     

Ndrg2 promoter hypermethylation triggered by helicobacter pylori infection correlates with poor patients survival in human gastric carcinoma

N-myc downstream regulated gene 2 (Ndrg2) is a candidate suppressor of cancer metastasis. We found that Ndrg2 promoter was frequently hypermethylated in gastric cancer cell lines and in 292 gastric tumor tissues. This resulted in down-regulation of Ndrg2 mRNA and protein. Ndrg2 promoter methylation was associated with H. pylori infection and worse prognosis of gastric cancer patients, which is an independent prognostic factor for the disease-free survival (DFS). We found that H. pylori silenced Ndrg2 by activating the NF-κB pathway and up-regulating DNMT3b, promoting gastric cancer progression. These findings uncover a previously unrecognized role for H. pylori infection in gastric cancer.     

Influence of Helicobacter pylori oncoprotein CagA in gastric cancer: A critical-reflective analysis

Gastric cancer is the fifth most common malignancy and third leading cancer-related cause of death worldwide. Helicobacter pylori is a Gram-negative bacterium that inhabits the gastric environment of 60.3% of the world’s population and represents the main risk factor for the onset of gastric neoplasms. CagA is the most important virulence factor in H. pylori, and is a translocated oncoprotein that induces morphofunctional modifications in gastric epithelial cells and a chronic inflammatory response that increases the risk of developing precancerous lesions. Upon translocation and tyrosine phosphorylation, CagA moves to the cell membrane and acts as a pathological scaffold protein that simultaneously interacts with multiple intracellular signaling pathways, thereby disrupting cell proliferation, differentiation and apoptosis. All these alterations in cell biology increase the risk of damaged cells acquiring pro-oncogenic genetic changes. In this sense, once gastric cancer sets in, its perpetuation is independent of the presence of the oncoprotein, characterizing a “hit-and-run” carcinogenic mechanism. Therefore, this review aims to describe H. pylori- and CagA-related oncogenic mechanisms, to update readers and discuss the novelties and perspectives in this field.     

幽门螺杆菌及其cagA因子与胃腺癌的关系

探讨ＨＰ与胃腺癌的相关性,特别是ｃａｇＡ因子胃腺癌的相关性。方法：利用血抗Ｈｐ－ＩｇＧ、ＢＵＴ、ＰＣＲ－Ｈｐ－ＤＮＡ３种方法检测２７０例病人耳垂血或胃粘膜活检组织中的Ｈｐ及其ｃａｇＡ基因。结果Ｈｐ感染率为６８．５２％（无性别差异）,ｃａｇＡ＾＋Ｈｐ感染率为５４．７３％（男性６４．００％〉女性４１．９４％,Ｐ〈０．０５）。     

S期激酶相关蛋白2在幽门螺杆菌L型致胃癌中的作用

目的：研究S期激酶相关蛋白2（S-phase kinase associated protein 2,Skp2）在幽门螺杆菌L型（Helicobacter pylori L-form,Hp-L型）感染致胃癌中所起的作用。方法：将胃癌BGC-823细胞与Hp-L型以不同比例共培养,在倒置显微镜下观察细胞形态学变化,并应用原位杂交和免疫组化分别检测Skp2 mRNA和蛋白在胃癌BGC-823细胞中的表达情况。同时收集慢性萎缩性胃炎（CAG）、胃肠腺化生（GIM）、胃不典型增生（GED）、胃癌（GCa）标本各40例,以40例轻度慢性浅表性胃炎（CSG）作为对照。应用革兰染色和免疫组化检测Hp-L型在上述组织中的感染情况;并进一步检测Hp-L型阳性组织中Skp2 mRNA和蛋白的表达情况。结果：Hp-L型作用BGC-823细胞后,倒置显微镜观察到细胞分裂增多,出现明显的生长加速现象;原位杂交和免疫组化检测发现BGC-823细胞中Skp2 mRNA和蛋白表达阳性率随细菌浓度的增加和作用时间的延长而逐渐增加（P〈0.05）。Hp-L型阳性组织中的Skp2mRNA和蛋白的表达阳性率按CAG、GIM、GED、GCa的顺序逐渐增加,但仅GCa组与CSG组间的差异具有统计学意义（P〈0.05）。结论：Skp2在Hp-L型感染的胃癌前病变及胃癌中均明显升高,提示其在胃癌的发生及发展中起着重要作用。     

Helicobacter pylori infection and gastric carcinogenesis in animal models

The effects of Helicobacter pylori infection on gastric disorders have been proven by many epidemiological and experimental studies. To explore the relationships between H. pylori infection and gastric carcinogenesis, many factors, including host responses, environmental status, and the virulence factors of the bacteria should be taken into account. Mongolian gerbils ( Meriones unguiculatus ) can be easily infected with H. pylori , and provide an excellent in-vivo experimental model to clarify the role of H. pylori in active gastritis, peptic ulcers, intestinal metaplasia, and gastric carcinoma. Studies have revealed that H. pylori infection markedly enhances all histological types of gastric cancers in gerbils treated with a chemical carcinogen. Eradication reduced the enhancing effect of H. pylori on gastric carcinogenesis, whereas a high-salt diet synergistically enhanced the effect of H. pylori . Various factors involving inflammation, cell proliferation, and cell differentiation could be examined with this experimental model to help elucidate this mechanisms of gastric carcinogenesis. Received: October 23, 2002 / Accepted: December 9, 2002 Acknowledgments We thank Dr. Toshiko Kumagai, Central Clinical Laboratories, Shinshu University Hospital; Dr. Atsushi Sugiyama, First Department of Surgery, Shinshu University; Professor Tsutomu Katsuyama, Department of Laboratory Medicine, Shinshu University School of Medicine; and Dr. Nobuyuki Shimizu and Professor Michio Kaminishi, Department of Gastrointestinal Surgery, Postgraduate School of Medicine, The University of Tokyo. Offprint requests to: M. Tatematsu     

From Helicobacter pylori infection to gastric cancer: Current evidence on the immune response

Gastric cancer (GC) is the result of a multifactorial process whose main components are infection by Helicobacter pylori (H. pylori), bacterial virulence factors, host immune response and environmental factors. The development of the neoplastic microenvironment also depends on genetic and epigenetic changes in oncogenes and tumor suppressor genes, which results in deregulation of cell signaling pathways and apoptosis process. This review summarizes the main aspects of the pathogenesis of GC and the immune response involved in chronic inflammation generated by H. pylori.     

幽门螺杆菌感染与胃癌及癌前病变中P21蛋白的表达

 用LSAB免疫组化法，对20例谓癌、22例异型增生、30例肠化生及13例正常组织进行了P21蛋白表达的检测。结果发现，胃癌、异型增生和肠化生的P21阳性者分别为13例（65.0%）,12例（60.0%）,11例（36.6%）,正常组织全部阴性；三种组织中，HP阳性病人的P21阳性率为41.6%（30/72）,明显高于HP阴性病人的8.3%（6/72）,有显着差别（P<0.01）.说明HP感染与P21过度表达存在着明显的相关性。提示HP感染可能通过ras癌基因的突变而参予致癌作用。     

Serum pepsinogen levels in gastric cancer patients and their relationship with Helicobacter pylori infection: a prospective study

Background: Our aim was to study the serum pepsinogen levels in gastric cancer patients in our population in relation to histology and the presence of Helicobacter pylori . Methods: Forty-six patients with gastric cancer and 70 controls were studied prospectively in a 1-year period. Serum levels of pepsinogen I (PG I), pepsinogen II (PG II), and gastrin were measured by radioimmunoassay. Results: The mean PG I levels for cancer patients and controls were 83.5 μg/l and 60.9 μg/l, respectively ( P = 0.03), the mean PG II levels were 27.2 μg/l and 12.1 μg/l respectively ( P < 0.0001). The PG I/II ratio was significantly lower in cancer patients ( P = 0.04) and in those with Helicobacter infection. Serum pepsinogen levels were not affected by any pathological characteristics. Histology showed that the prevalence of chronic gastritis, intestinal metaplasia, and gastric atrophy was 97%, 56%, and 15%, respectively. Conclusion: The prevalence of gastric atrophy is low in our population, and serum pepsinogen measurement is not useful as a screening tool for gastric cancer in this population. Received: July 8, 2002 / Accepted: September 2, 2002 Offprint requests to: J.B.-Y. So     

Promoter methylation of p16 associated with Helicobacter pylori infection in precancerous gastric lesions: a population-based study

To investigate the relationship between p16 methylation and Helicobacter pylori infection in precancerous gastric lesions, a population-based study was conducted in Linqu County, a high-risk area of gastric cancer in China. Methylation status of p16 was evaluated by methylation-specific polymerase chain reaction in 920 subjects with precancerous gastric lesions. H. pylori status was determined by 13C-urea breath test and the density of H. pylori in biopsy specimens used for detecting methylation status was assessed by the modified Giemsa stain. The frequency of p16 methylation was significantly higher in subjects with H. pylori positive than those with H. pylori negative in each category of gastric lesion (p<0.001, respectively). Compared with H. pylori negative, the odds ratios (ORs) of p16 methylation were markedly elevated in subjects with H. pylori positive for superficial gastritis (OR, 9.45; 95% confidence interval [CI]: 2.94-30.41), chronic atrophic gastritis (OR, 15.92; 95%CI: 7.60-33.36), intestinal metaplasia (OR, 4.46; 95%CI: 2.44-8.13), indefinite dysplasia (OR, 3.67; 95%CI: 1.90-7.10), and dysplasia (OR, 2.48; 95%CI: 1.02-5.99). Moreover, the frequencies of p16 methylation increased steadily with the severity of H. pylori density in gastric mucosa. Compared with H. pylori negative, the OR of p16 methylation was 1.02-16.13 times higher in subjects with mild H. pylori infection, and 2.69-38.73 times higher in those with moderate/severe infection, respectively. Our findings indicate that p16 methylation was significantly associated with H. pylori infection in precancerous gastric lesions, suggesting that H. pylori infection could potently induce methylation of p16 CpG island.     

Helicobacter pylori and gastric cancer

Helicobacter pylori is now well known as an important pathogen related to the development of gastric cancer. However, some clinicians still doubt the causal association of H. pylori with the development of gastric cancer. To summarize the recent clinical data on the link between H. pylori and gastric cancer, we reviewed related articles published over the past 3 years, after the award of the Nobel Prize for Physiology or Medicine to Drs. J.R. Warren and B.J. Marshall for the first culture and isolation of H. pylori and the investigation of their relevance to peptic ulcer disease. This updated summary of the relationship between H. pylori and gastric cancer highlights the strong link between the organism and the development of gastric cancer, and suggests eradication of this bacterial infection as a possible prophylactic measure against the development of this lethal malignancy. At present, clinicians and researchers in the field emphasize the strong need for H. pylori eradication from the human stomach.     

幽门螺杆菌感染与胃癌发生发展及预后的相关性研究

目的探讨胃癌患者幽门螺杆菌(H.pylori,HP)的感染与其临床病理参数和预后的关系,以及在胃癌发生、发展及预后中的作用。方法应用实时荧光定量PCR的相对定量法,检测2004-01-01-2007-12-31石河子大学医学院第一附属医院病理科存档的石蜡包埋胃癌组织标本118例及其32例相应癌旁组织的HP相对感染量。应用SPSS 17.0软件,采用非参数检验Mann-Whitney U和Kruskal-Wallis H检验以及Log-rank检验等多种统计学分析方法。结果118例胃癌组织的HP相对感染量为0.02~26.76,平均为8.73±6.50,32例相应癌旁组织为0.29~8.06,平均为4.28±2.53。胃癌组织中HP相对感染量与患者年龄、性别、组织学分型、分化程度及有无远处转移无关,P>0.05;与浸润深度(P=0.001)、淋巴结转移(P=0.005)和临床分期(P=0.005)相关;在同一胃癌患者中,癌组织HP相对感染量显著高于癌旁组织,P<0.001;HP相对感染量<1、1相似文献   

胃癌及其有关病变的幽门螺杆菌感染与抑癌基因表达的相关性研究

背景与目的:幽门螺杆菌(Helicobacterpylori,Hp)是确定的胃癌致癌因子,但其致癌的确切机制仍不清楚。p53、p21WAF1、p16为主要的细胞周期负调控基因。本研究旨在探讨胃癌及其有关病变中,上述3种抑癌基因的作用及其与幽门螺杆菌感染的关系。方法:应用HID-AB(pH2.5)-PAS、SP免疫组化染色及Warthin-Starry染色,对65例慢性萎缩性胃炎(chronicatrophicgastritis,CAG),93例肠上皮化生(intestinalmetaplasia,IM),94例胃上皮不典型增生(gastricepithelialdysplasia,GED)及60例胃癌(gastriccarcinoma,GC)中3种抑癌基因表达和幽门螺杆菌感染情况进行检测。结果:在胃癌发生的不同阶段,p53阳性表达率随病变发展而升高,在CAG、IMⅠ～Ⅱ、IMⅢ、GEDⅠ级、GEDⅡ～Ⅲ级及GC中分别为0、1.64%、6.25%、5.45%、23.08%、70.00%。p21WAF1和p16阳性表达率随病变发展而降低,p21WAF1阳性表达率分别为100%、95.08%、100%、100%、71.79%、45.00%,p16阳性表达率分别为83.08%、81.97%、78.13%、89.09%、69.23%、40.00%。三者表达在GEDⅡ～Ⅲ与GEDⅠ组间、GC与GEDⅡ～Ⅲ组间的差异均具有显著性(P<0.05)。同一病变中,Hp感染阳性组p53、p21WAF1及p16阳性表达率虽然高于Hp阴性组,但差异无显著性(P>0.05)。结论:p53突变及p21WAF1、p16失活     

Interaction of cyclooxygenase-2 promoter polymorphisms with Helicobacter pylori infection and risk of gastric cancer

Overexpression of cyclooxygenase (COX)-2 has been implicated in the development of cancer. This study aimed to evaluate the relationship between genetic variants in COX-2 promoter interacting with Helicobacter pylori and the susceptibility to gastric cancer (GC). Three COX-2 polymorphisms -1290A>G (rs689465), -1195G>A (rs689466), and -765G>C (rs20417) were genotyped in 323 GC patients and 944 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression model. In GC patients, the ORs were 2.33 (95% CI = 1.50-3.63) and 2.70 (95% CI = 1.68-4.33) for -1195AA and -765CG genotype carriers, respectively. Haplotype analysis showed all -1195A allele-containing haplotypes, except G(-1290)-A(-1195)-G(-765), were associated with increased risk for GC, compared with the A(-1290)-G(-1195)-G(-765) haplotype. Moreover, significant multiplicative and additive interactions were observed between H. pylori infection and all these three polymorphisms, and H. pylori-infected subjects carrying the variant allele of -1290A>G, -1195G>A, or -765G>C had increased risk of GC compared with non-H. pylori-infected subjects with wild-type allele (OR = 4.10, 95% CI = 1.90-8.83; OR = 3.46, 95% CI = 1.31-9.11; and OR = 3.32, 95% = 1.27-8.73, respectively). Our results suggested that the COX-2 promoter polymorphisms were associated with increased risk of GC, especially interacting with H. pylori infection.     

Genetic polymorphism in chemokine CCL22 and susceptibility to Helicobacter pylori infection‐related gastric carcinoma

BACKGROUND:

Gastric carcinoma is widely considered to be related to Helicobacter pylori infection, and the chemokine (C‐C motif) ligand 22 (CCL22) plays an important role in suppressing immune responses against H. pylori and tumor cells. In this study, the authors examined the association between single nucleotide polymorphisms (SNPs) in the CCL22 gene and the risk of gastric carcinoma.

METHODS:

Information on SNPs in the CCL22 coding region was obtained from the HapMap Project database. Genotypes were determined in a case‐control cohort that consisted of 1001 patients with gastric carcinoma and 1066 controls, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were computed by using a logistic regression model. Serum H. pylori antibody levels were measured by using an enzyme‐linked immunosorbent assay.

RESULTS:

The 16C→A SNP (reference SNP no. 4359426) in exon 1 of the CCL22 gene, which causes a 2 aspartate (2Asp) to 2 alanine (2Ala) substitution in the CCL22 protein, was associated with a significantly increased risk of gastric carcinoma. Individuals who were homozygous for the Ala/Ala genotype had an OR of 2.27 (95% CI, 1.28‐4.02) compared with individuals who had the Asp/Asp genotype. Stratification analysis indicated that the association was more pronounced among men (OR, 2.64; 95% CI, 1.29‐5.41) and among younger individuals (OR, 2.85; 95% CI, 1.36‐5.96) compared with women and older individuals. Moreover, a multiplicative joint effect between the CCL22 SNP and H. pylori infection that intensified the risk was observed (OR for the presence of both Ala/Ala genotype and H. pylori infection, 18.37; 95% CI, 2.30‐146.67).

CONCLUSIONS:

The results from this study suggested that the CCL22 polymorphism is associated with an increase risk of developing H. pylori infection‐related gastric carcinoma. Cancer 2009. © 2009 American Cancer Society.     

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.     

CD44v6在胃癌中的表达及其与幽门螺杆菌感染的关系

背景与目的:目前认为CD44v6在胃癌组织中有较高的表达率,并公认幽门螺杆菌(Helicobactor pylori,HP)感染为Ⅰ类胃癌致癌原,但迄今未见CD44v6与HP关系的文献报道。本文旨在探讨CD44v6在胃癌中的表达及其与HP感染的关系。方法:选取胃癌组织56例、癌旁非癌组织56例、非典型增生胃粘膜32例。CD44v6检测采用RT-PCR与Southern blot法;HP检测采用快速尿酶法与Warthin-Starry银染色;同时用ELISA测定56例胃癌患者血清中HP cagA抗体。结 果:胃粘膜HP阳性组中,转移性胃癌和非转移胃癌的CD44v6表达率分别达100％(12/12)和90.5％(19/21),明显高于癌旁非癌胃组织的48.6％(24/35)与非典型增生胃粘膜的23.6％(6/23);转移性胃癌与非转移胃癌的CD44v6表达率比较无显著差异(P>0.25),非典型增生胃粘膜与胃癌、癌旁非癌胃组织比较有非常显著性差异(P<0.005)。胃粘膜HP阴性组:在转移性胃癌、非转移胃癌、癌旁非癌组织和非典型增生CD44v6表达率分别是66.7％,51.4％,38.1％和18.1％,各组比较均无显著性差异。CD44v6表达与HP感染有密切关系(P<0.01)。肠型胃癌CD44v6表达与HP感染高于弥漫型胃癌(P>0.05)。胃癌患者血清HP cagA抗体阳性率高于胃癌组织HP感染率(P>0.05)。结论:CD44v6在胃癌中有较高的阳性率,与HP感染密切相关,可作为     

胃粘膜上皮异型增生细胞增殖活性及凋亡与幽门螺杆菌感染的关系

背景与目的:异型增生是胃癌的癌前病变,但其癌变机制目前仍不清楚,本文通过对异型增生自然转归过程中细胞增殖活性和凋亡变化及幽门螺杆菌(Helicobacterpylori,HP)感染状态的研究,探讨二者之间的关系及其对异型增生癌变的影响。方法:取12例正常胃粘膜(对照组)和105例有随访结果的胃粘膜异型增生胃镜活检标本〔其中高度异型增生35例(癌变30例、未癌变5例);低度异型增生70例(癌变18例、未癌变52例)〕。全部标本均采用TUNEL(terminaldeoxynucleotidyltransferasemediatednickendlabeling)法检测凋亡情况;采用免疫组化法检测增殖细胞核抗原(proliferatingcellnuclearantigen,PCNA)表达情况;采用多聚酶链反应(polymerasechainreaction,PCR)检测HP及其CagA(+)株感染状况。结果:异型增生的HP感染率为84.76%,与对照组的83.33%相比差异无统计学意义,但CagA(+)株感染率为85.39%,高于对照组的60.00%。HP(+)和CagA(+)病例的增殖指数分别较HP(-)和CagA(-)为高(P<0.05),异型增生中PCNA的异常与HP及CagA(+)株感染有关(P<0.05)。凋亡/增殖比的变化与Hp的CagA(+)株感染有关(P<0.05)。结论:胃粘膜异型增生的形成及其自然转归过程中,异型增生的细胞动力学异常与HP、CagA(+)株感染有关。     

Hp感染与胃癌中癌基因和抑癌基因蛋白表达的关系

目的研究Hp感染与胃癌发生的关系及其可能的致癌机制。方法经内镜和病理诊断的胃癌91例,用快速尿素酶试验,改良W-S银染色和PCR方法检测上述标本中Hp;以S-P免疫组织化学法检测P21、P53、C-mcy及C-erbB-2,并用阳性表达积分半定量和免疫组化图像分析进行比较。结果Hp阳性胃癌组(44例)的P21、P53、C-myc及C-erbB-2表达阳性率较Hp阴性胃癌组(47例)为高。Hp阳性组这4种癌基因蛋白的阳性表达积分、平均光密度和积分光密度均显著高于Hp阴性组(P<0.05～0.01)。结论Hp感染与胃癌中P21、P53、C-myc及C-erbB-2的异常表达密切相关,提示Hp感染可使胃粘膜细胞的癌基因活化和抑癌基因突变或失活,促进胃粘膜细胞恶性转化而导致胃癌发生。