胃幽门螺杆菌感染与抑癌基因失活的关系

目的探讨胃癌及癌前病变组织中幽门螺杆菌(H.pylori)感染与抑癌基因失活间的相互关系.方法运用DNA-PCR技术检测H.Pylori感染,采用PCR-RFLP,PCR-SSCP,RT-PCR及免疫组化技术分析182例胃癌及癌前病变及正常胃粘膜中抑癌基因APC,MCC,DCC,YNZ22及p53基因的杂合缺失、突变、mRNA及蛋白异常表达.结果胃癌及癌前病变组织中H.pylori的感染率(IM61.7%,Dys 63.3%,GC 42.3%)显著高于正常胃粘膜(17.5%,P＜0.05).但胃癌及癌前病变间H.pylori感染率无显著差别(P＞0.05),胃肠两型胃癌中H.pylori感染率分别为47.1%及42.2%,两者无显著差别(P＞0.05).胃癌及癌前病变组织中存在多种抑癌基因失活.H.pylori感染与癌前病变-肠化生中APC基因异常蛋白表达有关(Hp+43.2%vsHp-13.0%,P＜0.05).胃癌组织H.pylori感染阳性组中APC基因突变(50.0%)及蛋白表达(63.6%)、p53基因蛋白表达率(59.1%)显著高于阴性组(vs16.7%,P＜0.05;vs30.0%,P＜0.01;vs20.0%,P＜0.01).结论幽门螺杆菌感染及多种抑癌基因失活可能与胃癌的发生发展相关,H.pylori感染与APC,p53基因失活可能相关.     

Dynamic expression of pepsinogen C in gastric cancer, precancerous lesions and Helicobacter pylori associated gastric diseases

AIM: To investigate the relationship between the expression of pepsinogen C (PGC) and gastric cancer, precancerous diseases, and Helicobacter pylori (H pylori) infection. METHODS: The expression of PGC was determined by immunohistochemistry method in 430 cases of gastric mucosa. H3 Pylori infection was determined by HE staining, PCR and ELISA in 318 specimens. RESULTS: The positive rate of PGC expression in 54 cases of normal gastric mucosa was 100%. The positive rates of PGC expression in superficial gastritis or gastric ulcer or erosion, atrophic gastritis or gastric dysplasia and gastric cancer decreased significantly in sequence (P<0.05; 100%/89.2% vs 14.3%/15.2% vs 2.4%). The over-expression rate of PGC in group of superficial gastritis with H pyloriinfection was higher than that in group without H pylori infection (P<0.05; x2= 0.032 28/33 vs 15/25). The positive rate of PGC expression in group of atrophic gastritis with H pylori infection was lower than that in group without H pylori infection (P<0.01; x2 = 0.003 4/61 vs9/30), and in dysplasia and gastric cancer. CONCLUSION: The level of PGC expression has a close relationship with the degree of malignancy of gastric mucosa and development of gastric lesions. There is a relationship between H pylori infection and expression of antigen PGC in gastric mucosa, the positive rate of PGC expression increases in early stage of gastric lesions with H pylori infection such as gastric inflammation and decreases during the late stage such as precancerous diseases and gastric cancer. PGC-negative cases with H py/ori-positive gastric lesions should be given special attention.     

Treatment of Helicobacter pylori and prevention of gastric cancer

Gastric cancer is the second commonest fatal malignancy in the world with a high incidence in China. Helicobacter pylori infection is an important factor in the pathogenesis of gastric cancer. Epidemiological studies have shown a strong causal relationship between H. pylori infection and gastric cancer. Animal studies also show that eradication of H. pylori infection, especially at the early stage, is effective in preventing H. pylori-related gastric carcinogenesis. H. pylori eradication leads to regression and prevents the progression of gastric precancerous lesions, but only in a minority of cases. H. pylori eradication appears to be the most promising approach in gastric cancer prevention. The current available data in human studies showed that H. pylori eradication can reduce the risk of developing gastric cancer and this strategy is more useful in patients without atrophic gastritis or intestinal metaplasia. A longer follow-up and additional studies are needed for better understanding this issue.     

Anti-Helicobacterpylori therapy followed by celecoxib on progression of gastric precancerous lesions

AIM： To evaluate whether celecoxib, a selective cyclooxygenase 2 （COX-2） inhibitor, could reduce the severity of gastric precancerous lesions following Hel/cobacter pylori （H pylorl） eradication. METHODS： H pylori-eradicated patients with gastric precancerous lesions randomly received either celecoxib （n = 30） or placebo （n = 30） for up to 3 mo. COX-2 expression and activity was determined by immunostaining and prostaglandin E2 （PGE2） assay, cell proliferation by Ki-67 immunostaining, apoptosis by TUNEL staining and angiogenesis by microvascular density （MVD） assay using CD31 staining.RESULTS： COX-2 protein expression was significantly increased in gastric precancerous lesions （atrophy, intestinal metaplasia and dysplasia, respectively） compared with chronic gastritis, and was concomitant with an increase in cell proliferation and angiogenesis. A significant improvement in precancerous lesions was observed in patients who received celecoxib compared with those who received placebo （P 〈 0.001）. Of these three changes, 84.6% of sites with dysplasia regressed in patients treated with celecoxib （P = 0.002） compared with 60% in the placebo group, suggesting that celecoxib was effective on the regression of dysplasia. COX-2 protein expression （P 〈 0.001） and COX-2 activity （P 〈 0.001） in the gastric tissues were consistently lower in celecoxib-treated patients compared with the placebo-treated subjects. Moreover, it was also shown that celecoxib suppressed cell proliferation （P 〈 0.01）, induced cell apoptosis （P 〈 0.01） and inhibited angiogenesis with decreased MVD （P 〈 0.001）. However, all of these effects were not seen in placebo-treated subjects. Furthermore, COX-2 inhibition resulted in the up-regulation of PPARy expression, a protective molecule with anti-neoplastic effects. CONCLUSION： H pylori eradication therapy followed by celecoxib treatment improves gastric precancerous lesions by inhibiting COX-2 activity, inducing apoptosis, and suppressing cell proliferation and angiogenesis.     

H pylori （CagA） and Epstein-Barr virus infection in gastric carcinomas：Correlation with p53 mutation and c-Myc,Bcl-2 and Bax expression

AIM： To investigate the interrelationship between H pylori and Epstein-Barr virus （EBV） infection in the gastric carcinogenesis having in focus the p53 mutation and the c-Myc, Bcl-2 and Bax expression. METHODS： seventy-one gastric carcinoma tissues were assessed by polymerase chain reaction （PCR） for H pylori and in situ hybridization for EBV. c-Myc, Bcl-2 and Bax expression were detected by immunohistochemistry and single-stranded conformational polymorphism （SSCP） for p53 mutation. RESULTS： The positivity rates for H pylori and EBV were 94.4% and 8.45%, respectively. The majority of the cases displayed only the H pylori presence. All EBV positive cases were also H pylori positive. None infectious agent was observed in 5.55% of the cases. The intestinal type tumor was more frequent in the co-infected and non-infected groups. The female predominated in the non-infected group showing statistical significance （70.4% vs 29.6%, P=0.039）. The Bcl-2 was only detected in the group exclusively infected by H pylori. However, c-Myc and Bax were detected in the three groups but with a low frequency in the co-infected group. Mutation of p53 was present in all groups, with the highest frequencies in the H pylori positive groups. CONCLUSION： The frequency of H pylori infection in gastric carcinomas was high. The presented data indicated that gastric carcinogenesis has different pathways depending of the presence of the two investigated infectious agents, suggesting a possible involvement of H pylori with apoptotic process. The low expression of c-Myc and Bax in the EBV-positive groups suggests that EBV may inhibit the expression of these proteins. Nevertheless, p53 mutation shows to be a relevant alteration, independent of both infectious agents.     

Can gastric cancer be prevented by Helicobacter pylori eradication?

Helicobacter pylori infection always causes chronic gastritis and triggers several gastroduodenal pathologies ranging from peptic ulcer disease to gastric cancer. It is well established that H. pylori eradication decreases the incidence of gastroduodenal ulcer and its recurrence. However, despite being accepted as the critical risk factor for gastric cancer, there is no conclusive evidence that H. pylori eradication decreases the incidence of gastric cancer. Bacterial virulence characteristics, as well as genetic predisposition of the host in conjunction with certain environmental conditions, are the major factors which influence the development of gastric cancer. Preclinical and clinical data suggest that reversibility of precancerous lesions (atrophic gastritis and intestinal metaplasia) is possible in some patients after H. pylori eradication. Since neoplastic lesions do not progress - or even regress in some cases - after H. pylori eradication, eradication therapy should be considered even in patients with precancerous lesions. Nonetheless, progression of atrophic gastritis and intestinal metaplasia into cancer has been also demonstrated in patients after H. pylori eradication, suggesting that there might be a point of no return where genetic changes have already happened and are irreversible despite elimination of the triggering carcinogen (H. pylori). At the present time the clinical decision to treat a patient is based on established risk profiles. A general screen-and-treat policy, although desirable, currently awaits a less complex treatment regimen.     

幽门螺杆菌感染诱导胃黏膜上皮细胞凋亡及端粒酶逆转录酶表达

目的研究幽门螺杆菌（Hp）根除前后胃黏膜上皮细胞凋亡和端粒酶逆转录酶（hTERT）表达及其与bcl-2、c-myc蛋白表达的关系。方法采用脱氧核糖核酸末端转移酶介导的缺口末端标记（TUNEL）技术及免疫组化染色方法检测39例却Hp性患者根除治疗及21例却阴性患者对症治疗前后胃黏膜上皮细胞凋亡、hTERT、bcl-2、c—myc蛋白表达的变化。结果治疗前却阳性者胃黏膜上皮细胞凋亡指数为16．2％，显著高于却阴性者（P〈0．05）；却阳性者hTERT、c—myc蛋白表达显著高于却阴性者（53．8％比23．8％；53．8％比28．6％，P〈0．05）。邯根除者治疗后胃黏膜上皮细胞凋亡、hTERT及bcl-2、c—myc蛋白表达与根除前相比均显著下降（16．9％比9．0％；59．3％比22．2％；59．3％比25．9％；59．3％比14．8％，P〈0．01），且与却阴性对照组相比差异无统计学意义（P〈0．05）；而邯未根治组及对照组上述指标均无显著变化。治疗前bcl-2、c—myc蛋白与hTERT呈显著正相关，秩相关系数r分别为0．269、0．474（P〈0．05）。结论却感染诱导细胞凋亡及hTERT过度表达，使胃黏膜不稳定性增加。根除却可纠正细胞凋亡失调，使hTERT表达下降或消失，从而降低胃癌发生的可能性。bcl-2及c—myc蛋白对hTERT表达可能具有调控作用。     

Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis

OBJECTIVES: Helicobacter pylori is an identified carcinogen for gastric cancer, however, the underlying mechanisms remain to be defined. In this review, we sought to elucidate the role of apoptosis in gastric carcinogenesis, to determine the influence of H. pylori infection on apoptosis, and finally to provide insights into the mechanisms by which H. pylori may lead to gastric carcinogenesis. METHODS: A broad-based MEDLINE and Current Contents literature search was performed to identify relevant publications between 1966 and March 2000 addressing H. pylori infection, apoptosis, cell proliferation, gastric carcinoma, oncogenes, and tumor suppressor genes, as well as the products of these genes. Abstracts from recent major conferences that provided adequate additional data were also included. RESULTS: Apoptotic cells are rare in the glandular neck region (the generative cell zone) of normal gastric mucosa. With progression of atrophic gastritis, the generative cell zone shifts downward and a relatively large number of apoptotic cells occur. In intestinalized glands, both apoptotic cells and proliferative cells are present in deeper portions of the glands, corresponding to the generative zone. A higher frequency of apoptosis has been observed in gastric dysplasia than in coexisting gastric carcinomas, whereas the number of proliferative cells is significantly higher in gastric carcinoma than in dysplasia. Upregulation of oncogene bcl-2 in premalignant lesions and "downregulation" of the gene after malignant change is probably a common event. Accumulation of p53 protein is first detected in dysplasia, although mutation of the pS3 gene may occur in intestinal metaplasia. H. pylori infection induces apoptosis in gastric epithelial cells, which returns to normal after eradication of the infection. Numerous molecules produced by H. pylori including cytotoxin (VacA), lipopolysaccharide, monochloramine, and nitric oxide may directly induce apoptosis. Moreover, H. pylori-stimulated host inflammatory/immune responses lead to release of a large amount of cytokines. Cytokines produced by type 1 T helper cells, such as TNF-alpha and IFN-gamma, markedly potentiate apoptosis. Gastric cell proliferation is significantly higher in patients with H. pylori infection than in normal controls, and eradication of the infection leads to a reduction in cell proliferation. Apoptosis and cell proliferation are also increased in precancerous lesions such as gastric atrophy, intestinal metaplasia, and dysplasia in the presence of H. pylori infection. However, H. pylori-induced apoptosis may no longer be cell cycle-dependent in these lesions because of the occurrence of alterations and mutations of apoptosis-regulating genes, resulting in a loss of balance between apoptosis and cell proliferation. CONCLUSIONS: It is hypothesized that H. pylori-induced apoptosis may play a key role in gastric carcinogenesis by increasing cell proliferation and/or resulting in gastric atrophy.     

根除幽门螺杆菌对端粒酶相关基因及c-myc蛋白表达的影响

目的　研究幽门螺杆菌 (Hp)根除前后端粒酶相关基因及c myc蛋白表达的变化 ,分析端粒酶催化亚单位 (hTERT)、端粒酶RNA(hTR)及c myc蛋白表达的关系。 方法　采用RNA原位核酸杂交和免疫组化法对 39例Hp阳性患者根除治疗及 2 1例Hp阴性患者对症治疗前后hTR、hTERT及c myc蛋白表达进行原位观察和比较。 结果　治疗前Hp阳性者hTR、hTERT及c myc蛋白阳性率显著高于Hp阴性者 (5 1.3%比 19.0 % ,5 3.8%比 2 3.8% ,5 3.8%比 2 8.6 % ,P <0 .0 5 )。Hp根除者治疗后hTR、hTERT及c myc蛋白阳性率较治疗前显著下降 (5 5 .5 %比 2 2 .2 % ,5 9.3%比 2 2 .2 % ,5 9.3%比14 .8% ,P <0 .0 5 ) ,且与Hp阴性对照组相比差异无显著性 ;而Hp未根除者及Hp阴性对照组治疗前后上述指标阳性率变化差异均无显著性 (P >0 .0 5 )。治疗前hTERT与hTR、hTERT与c myc蛋白表达均呈显著正相关 ,秩相关系数rs 分别为 0 .4 5和 0 .4 7(P <0 .0 1)。结论　Hp感染可通过诱导c myc蛋白过度表达使hTERT表达上调 ,导致端粒酶激活 ,使胃黏膜易于癌变。根除Hp可使端粒酶相关基因及c myc蛋白表达下降或消失 ,从而降低胃黏膜癌变的危险性。     

Effect of Helicobacter pylori infection on expression of Bcl-2 family members in gastric adenocarcinoma

AIM: To investigate the effect of Helicobacter pylori (H pylori) infection on the expressions of Bcl-2 family members in gastric adenocarcinoma. METHODS: Gastric adenocarcinoma and resection margin tissues of 95 patients were studied. Semi-quantitative RT-PCR was used to measure Bid, Bax and Bcl-2 mRNA expressions. RESULTS: Expressions of Bid and Bax in gastric adenocarcinoma tissues without H pylori infection, with cagA- H pylori infection and cagA+ H pylori infection increased significantly in turn (Bid, 0.304, 0.422 and 0.855 respectively, P<0.05; Bax, 0.309, 0.650 and 0.979 respectively, P<0.05). Bcl-2 mRNA levels increased significantly in gastric adenocarcinoma tissues with cagA- H pylori infection and cagA+ H pylori infection, compared with those without H pylori infection (0.696 and 0.849 vs 0.411, P<0.05). Expressions of Bid, Bax and Bcl-2 in resection margin tissues without H pylori infection, with cagA- H pylori infection and cagA+ H pylori infection increased significantly in turn (Bid, 0.377, 0.686 and 0.939 respectively, P<0.05; Bax, 0.353, 0.645 and 1.001 respectively, P<0.05; Bcl-2, 0.371, 0.487 and 0.619 respectively, P<0.05). In H pylori negative specimens, expressions of Bid and Bax correlated negatively with that of Bcl-2 respectively in adenocarcinoma tissues (Bid vs Bcl-2, r=-0.409, P<0.05; Bax vs Bcl-2, r=-0.451, P<0.05). In H pylori positive specimens, expressions of Bid and Bax did not correlate with that of Bcl-2 in adenocarcinoma tissues (Bid vs Bcl-2, r=0.187, P>0.05; Bax vs Bcl-2, r=0.201, P>0.05), but correlated positively with that of Bcl-2 respectively in resection margin tissues (Bid vs Bcl-2, r=0.331, P<0.05; Bax vs Bcl-2, r=0.295, P<0.05). CONCLUSION: H pylori may enhance Bid, Bax and Bcl-2 mRNA levels and cause deregulation of these apoptosis-associated genes expressions, which may play a role during development of gastric adenocarcinoma induced by H pylori.     

Expression of gastric cancer—associated MG7 antigen in gastric cancer,precancerous lesions and H.pylori—associated gastric diseases

AIM: To investigate the relationship between the antigen MG7 antigen expression and gastric cancer as well as precancerous condition; to study the relationship between the MG7 antigen expression and H. pyloriinfection in benign gastric lesions in order to find out the effect of H. pylori infection on the process of gastric cancer development.METHODS: The level of MG7 antigen expression was determined by immunohistochemical method in 383 gastric biopsied materials. The intestinal metaplasia was determined by histochemistry method. The H. pyloriinfection was determined by HE stain, PCR and ELISA in 291 specimens, among which only 34 cases of H. pylori-associated gastric lesions were followed up.RESULTS: The positive rate of MG7 expression in normal gastric mucosa, intestinal metaplasia, dysplasia and gastric cancer increased gradually in ascending order (P＜0.01). The positive rate of MG7 antigen expression in type Ⅲ intestinal metaplasia of gastric mucosa was higher than that of type Ⅰand Ⅱ intestinal metaplasia, being highly significant (P＜0.05).The positive rate of MG7 antigen expression in superficial gastritis, atrophic gastritis and gastric cancer increased gradually (11.9 %, 64.8 %, 91.2 %, P＜0.01). There was no significant difference between H.pylori-negative and H. pyloripositive intestinal metaplasia, atrophic gastritis and dysplasia of gastric epithelium in the positive rate of MG7 antigen expression. There was no expression of MG7 antigen in H. pylori-negative superficial gastritis. The positive rate of MG7 expression in H. pylori-positive superficial gastritis was 20.5 %, and the difference between them was significant (P＜0.05). During following up, one of the three H. pylori negative cases turned positive again, and its MG7 antigen expression turned to be stronger correspondingly. 3 of 31 H. pyloripositive cases were detected as early gastric cancer, among which one with "+++" MG7 antigen expression was diminished after H. pylori eradication.CONCLUSION: MG7 antigen expression is highly specific in gastric cancer and can be used as a good marker for screening of gastric cancer; type Ⅲ intestinal metaplasia, atrophic gastritis and dysplasia should be followed up and MG7 antigen expression has high clinical value in the dynamic follow-up study; although the positive -MG7 in positiveH. pylorisuperficial gastritis show benign morphology in features, there is still the potential risk of developing into gastric cancer, hence special attention should be paid to those showing increasing MG7 antigen expression.     

胃黏膜病变演化过程中抗氧化蛋白Peroxiredoxin6的表达及其与幽门螺杆菌感染的关系

目的探讨胃黏膜病变演化过程中抗氧化蛋白Peroxiredoxin 6(Prx6)表达水平变化及其与幽门螺杆菌(H.pylori)感染的关系。方法根据组织形态学将104例临床内镜检查活检标本分为慢性浅表性胃炎(33例)、慢性萎缩性胃炎(25例)、肠上皮化生(32例)及异型增生(14例)4组。用免疫组织化学方法检测组织标本中Prx6的表达水平。用快速尿素酶试验及Warthin-Starry银染检测H.pylori感染。结果 Prx6在慢性浅表性胃炎、慢性萎缩性胃炎、肠上皮化生、异型增生组的阳性表达率分别为39.4%(13/33)、80.0%(20/25)、93.8%(30/32)、92.9%(13/14),过表达率分别为15.2%(5/33)、44.0%(11/25)、81.3%(26/32)、85.7%(12/14)。慢性浅表性胃炎、慢性萎缩性胃炎组H.pylori阳性者Prx6阳性表达率显著高于H.pylori阴性者(P<0.05),肠上皮化生组Prx6的表达在H.pylori阳性者和阴性者无显著差异(P>0.05)。结论在胃黏膜病变演化过程中,Prx6的表达随着胃黏膜病变的进展而增加,H.pylori在胃黏膜病变演化的早期阶段促进了Prx6的表达。     

Helicobacter pylori-induced inflammation masks the underlying presence of low-grade dysplasia on gastric lesions

BACKGROUND Helicobacter pylori(H. pylori) infection has been associated with a long-term risk of precancerous gastric conditions(PGC) even after H. pylori eradication.AIM To investigate the efficacy of High-Resolution White-Light Endoscopy with Narrow-Band Imaging in detecting PGC, before/after H. pylori eradication.METHODS We studied 85 consecutive patients with H. pylori-related gastritis with/without PGC before and 6 mo after proven H. pylori eradication. Kimura-Takemoto modified and endoscopic grading of gastric intestinal metaplasia classifications, were applied to assess the endoscopic extension of atrophy and intestinal metaplasia. The histological result was considered to be the gold standard. The Sydney System, the Operative-Link on Gastritis-Assessment, and the OperativeLink on Gastric-Intestinal Metaplasia were used for defining histological gastritis, atrophy and intestinal metaplasia, whereas dysplasia was graded according to World Health Organization classification. Serum anti-parietal cell antibody and anti-intrinsic factor were measured when autoimmune atrophic gastritis was suspected.RESULTS After H. pylori eradication histological signs of mononuclear/polymorphonuclear cell infiltration and Mucosal Associated Lymphoid Tissue-hyperplasia, disappeared or decreased in 100% and 96.5% of patients respectively, whereas the Operative-Link on Gastritis-Assessment and Operative-Link on Gastric-Intestinal Metaplasia stages did not change. Low-Grade Dysplasia prevalence was similar on random biopsies before and after H. pylori eradication(17.6% vs 10.6%, P = 0.19), but increased in patients with visible lesions(0% vs 22.4%, P 0.0001). At a multivariate analysis, the probability for detecting dysplasia after resolution of H. pylori-related active inflammation was higher in patients with regression or reduction of Mucosal Associated Lymphoid Tissue hyperplasia, greater alcohol consumption, and anti-parietal cell antibody and/or anti-intrinsic factor positivity [odds ratio(OR) = 3.88, 95% confidence interval(CI): 1.31-11.49, P = 0.01; OR = 3.10, 95%CI: 1.05-9.12, P = 0.04 and OR = 5.47, 95%CI: 1.33-22.39, P 0.04, respectively].CONCLUSION High-Resolution White-Light Endoscopy with Narrow-Band Imaging allows an accurate diagnosis of Low-Grade Dysplasia on visible lesions after regression of H. pylori-induced chronic gastritis. Patients with an overlap between autoimmune/H. pylori-induced gastritis may require more extensive gastric mapping.     

Apoptosis, proliferation and p53 gene expression of H. pylori associated gastric epithelial lesions

AIM:To study the relationship between Helicobacter pylori(H.pylori)and gaatric carcinoma and its possiblepathogenesis by H.pylori.METHODS:DNEL technique and immunohistochemicaltechnique were used to study the state of apoptosis,proliferation and p53 gone expression.A total of 100 gastricmucosal biopsy specimens,including 20 normal mucosa,30H.pylori-negative and 30 H.pylori-positive gastricprecancerous lesions along with 20 gastric carcinomas werestudied.RESULTS:There were several apoptotic cells in thesuperficial epithelium and a few proliferative cells within theneck of gestric glands,and no p53 protein expression innormal mucosa.In gestric carcinoma,there ware fewapoptotic cells,while there were a large number ofproliferative cells,and expression of p53 proteinsignificantly was increased.In the phase of metaplasia,theapoptotic index(Al,4.36%±1.95%),proliferative index(Pl,19.11%±6.79%)and positivity of p53 expression(46.7%)in H.pylori-positive group ware higher than thosein normal mucosa(P<0.01).Al in H.pylori-positive groupwas higher than that in H.pylori-negative group(3.81%±1.76%),Pl in H.pylori-positive group was higher than thatin H.pylori-negative group(12.23%±5.63%,P<0.01).Inthe phase of dysplasia,Al(2.31%±1.10%) in H.pylori-positive group was lower(3.05%±1.29%)than that in H.pylori-negative group,but Pl(33.89%±11.65%)wassignificantly higher(22.09±8018%,P<0.01).In phases ofmetaplasia,dysplasia and gastric cancer in the H.pylori-positive group,Als had an evidently greduall decreasingtrend(P<0.01),while Pls had an evidently gradualincreasing trend(P<0.05 or P<0.01),and there was alsoa trend of gradual increase in the expression of p53 gone.CONCLUSION:In the course of the formation of gastriccarcinoma,proliferation of gastric mucosa can be greatlyIncreased by H.pylori,and H.pylori can induce apoptosisin the phase of metaplasia,but in the phase of dysplesia H.pylorl can inhibit cellular apptosis.And H.pylori infectioncan strengthen the expression of mutated p53 gene.     

根除幽门螺杆菌在预防胃癌中的作用

胃癌在全球恶性肿瘤致死亡的原因中位居第二位,幽门螺杆菌（H．pylori）感染是胃癌发生的重要病因。动物研究显示根除H.pylori,特别是在早期阶段,能有效预防胃癌的发生。部分病例通过根除npylori可阻止胃癌前病变的发展并可能使其逆转。最新研究表明根除H．pylori可降低胃癌发生的风险,对无萎缩或肠化生者可能尤其有效。本文就根除H．p）tori在预防胃癌中作用的研究进展作一综述。     

Eradication of Helicobacter pylori normalizes elevated mucosal levels of epidermal growth factor and its receptor

OBJECTIVE: Helicobacter pylori (H. pylori) infection has been linked to gastric cancer. The factors that promote carcinogenesis remain unknown. Epidermal growth factor (EGF) has been shown to be a potent epithelial mitogen and oncoprotein when sustained over expression occurs. Our aim was to compare gastric mucosal levels of EGF and its receptor (EGFR) among controls, H. pylori infected subjects, and subjects following H. pylori eradication using quantitative flow cytometric analysis. METHODS: Patients referred for evaluation of dyspepsia underwent EGD and six antral biopsies were performed (two each for rapid urease testing (RUT), histopathology, and flow cytometry). Controls were those found to be H. pylori negative while subjects had confirmed infection. The study patients were treated, then had repeat EGD with biopsies. RESULTS: There were 17 controls and 28 cases. Mean EGF and EGFR values were 2.69 and 2.46 for controls and 4.67 and 4.64 for subjects. Subjects' mean EGF was 73% higher (p = .035) and EGFR was 88% higher (p = 0.029) than controls. After treatment, the subjects' mean values declined 55% (p = 0.0001) for EGF and 40% (p = 0.002) for EGFR. Three subjects had persistent infection and showed no change in their EGF/EGFR levels. No difference was found among factor levels with respect to endoscopic findings. CONCLUSIONS: Both EGF and EGFR from gastric antral biopsies are increased nearly 2-fold in infection with H. pylori. Infection eradication reduces levels of both factors to those of controls. One major pathogenic mechanism for gastric mucosal hyperproliferation and possibly carcinogenesis related to H. pylori may be the over expression of EGF and increased receptor density of EGFR on gastric mucosal cells.     

胃粘膜癌前病变中幽门螺杆菌与c-met原癌基因蛋白表达关系的研究

为研究Hp感染后胃粘膜细胞中c-met原癌基因蛋白表达的情况,了解Hp在胃癌发生过程中的作用,对110例经病理证实为慢性胃炎的病人用免疫组化方法检测了胃粘膜细胞中e-met原癌基因蛋白表达情况。结果表明,在浅表性胃炎、萎缩性胃炎、肠化生及异型增生中,e-met原癌基因蛋白的表达率分别为22.2％、44.1％、67.5％和61.9％。过表达率分别为5.5％、26.4％、37.8％和38.1％。Hp感染后c-met原癌基因蛋白表达率较末感染者高,分别为63％及32％,在萎缩,肠化生及异型增生等癌前病变中Hp感染者与未感染者表达率分别为58.9％及29.7％(P<0.005)。本研究结果显示,随着病变的进展,c-met原癌基因的表达随之增加,从而说明Hp感染对c-met原癌基因蛋白表达有一定的影响,Hp启动了胃癌发展的早期阶段,也可能推进胃癌的发展过程。     

Helicobacter pylori infection generated gastric cancer through p53-Rb tumor-suppressor system mutation and telomerase reactivation

AIM: To investigate the relationship between Helicobacterpylori (H. pylori) infection and the expressions of the p53,Rb, c-myc, bcl-2 and hTERT mRNA in a series of diseasesfrom chronic gastritis (CG), intestinal metaplasia type Ⅰ or Ⅱ(IMⅠ-Ⅱ), intestinal metaplasia type Ⅲ (IMⅢ), mild or modestdysplasia (DysⅠ-Ⅱ), severe dysplasia (DysⅢ) to gastric cancer(GC) and to elucidate the mechanism of gastriccarcinogenesis relating to H.pyloriinfection.METHODS: 272 cases between 1998 and 2001 wereavailable for the study including 42 cases of CG, 46 cases ofIMⅠ-Ⅱ, 25 cases of IMⅢ, 48 cases of DysⅠ-Ⅱ, 27 cases ofDysⅢ, 84 cases of GC.-H. pyloriinfection and the expressionsof p53, Rb, c-myc, bcl-2 were detected by means ofstreptavidin-peroxidase (SP) immunohistochemical method.HTERT mRNA was detected byin situ hybridization(ISH).RESULTS: The expressions of p53, Rb, c-myc, hTERT mRNAand bcl-2 were higher in the GC than in CG, IN, Dys. Theexpression of c-myc was higher in IMⅢ with-H.pyloriinfection(10/16) than that without infection (1/9) and the positive ratein DysⅠ-Ⅱ and DysⅢ with-H.pyloriinfection was 18/30 and 13/17, respectively, higher than that without infection (4/18 and3/10, respectively). In our experiment mutated p53 had noassociation with H.pyloriinfection, theexpression of Rb wasassociated with-H. pyloriinfection in GC, but the p53-Rb tumor-suppressor system abnormal in DysⅠ-Ⅱ cases, DysⅢⅡ and GCcases with H. pyloriinfection was 21/30, 15/17 and 48/48respecively, higher than non-infection groups (4/18, 3/10, 28/36). Furthermore the level of hTERT mRNA in GC with H. pyloriinfection (47/48) was higher than that without infection (30/36), however the relationship between bcl-2 and H. pyloriwasonly in IMⅢ. C-myc had a close association with hTERT mRNAin DysⅢ and GC (P＝0.0 253,0.0 305 respectively).CONCLUSION: In the gastric carcinogenesis, H. pylorimightcause the severe imbalance of proliferation and apoptosisin the precancerous lesions (IMⅢ and GysⅢ) first, leadingto p53-Rb tumor-suppressor system mutation and telomerasereactivation, and finally causes gastric cancer.