幽门螺杆菌感染诱导胃粘膜环氧化酶-2表达

目的 探讨幽门螺杆菌（Hp)感染对胃粘膜环氧化酶－2（COX－2）表达的影响。方法 27例无任何症状健康检查者，经胃镜采取胃窦部粘膜组织，用于Hp检测、病理组织学检查及免疫组织化学检查COX－2的表达。结果 18例Hp感染者胃粘膜上皮细胞和炎症细胞表达COX－2，而9例Hp阴性者胃粘膜均不表达COX－2。结论 Hp感染诱导胃粘膜COX－2表达。     

Elevated cyclooxygenase-2 expression in patients with early gastric cancer in the gastric pylorus

Background Duodenogastric reflux after surgery increases the risk of gastric carcinoma. To determine whether bile reflux influences the development of gastric cancer in patients who have not had surgery, we compared cyclooxygenase-2 (COX-2) immunoreactivity in early gastric cancer originating from the gastric pylorus and that originating from other locations. We also examined the effects of bile acids on the expression and activity of COX-2 in gastric cells in vitro.Methods Tumor sections from 79 patients who underwent endoscopic mucosal resection for early intestinal-type gastric carcinoma were stained using a COX-2-specific monoclonal antibody. Immunoblotting of COX-2 was used to assess the effects of bile acids on COX-2 expression and activity in human gastric cell lines.Results Among the 79 early gastric cancer lesions studied, 13 (16%) arose in the gastric pylorus. In this group, COX-2 immunoreactivity was negative to weak in 38% (5 of 13 lesions) and moderate to strong in 62% (8 of 13 lesions). In the control group, COX-2 immunoreactivity was negative to weak in 70% (46 of 66 lesions) and moderate to strong in 30% (20 of 66 lesions). COX-2 expression was significantly elevated in early gastric cancer located in the gastric pylorus, compared with that in the other locations. In human gastric cell lines, bile acids induced COX-2 expression, mediated by the ERK 1/2 mitogen-activated protein kinase pathway.Conclusions COX-2 expression is elevated in early gastric cancer of the gastric pylorus, a common site of gastric cancer. Bile acids induced COX-2 expression in human gastric cell lines, suggesting a role of bile reflux in gastric carcinogenesis.     

Mechanism and clinical significance of cyclooxygenase-2 expression in gastric cancer

AIM: To determine the correlation between methylation status of 5' CpG island of cyclooxygenase-2 (COX-2) gene and protein expression in gastric cancer tissues for distinguishing the molecular characters of gastric cancers. METHODS: Methylation status of 5' CpG island of COX-2 gene was studied by PCR amplification after HpaⅡ and Hha I restrictive enzyme digestion;COX-2 expression was evaluated by immunohistochemical method. RESULTS: Hpa Ⅱ and HhaI site were all methylated in 12 normal gastric mucosa tissues, whereas they were demethylated in 77.27% (34/44) and 84.09% (37/44) gastric cancer tissues,respectively.Expression of COX-2 was detected in 68.18% (30/44) gastric cancer tissues, but no expression was found in normal gastric mucosa tissues. In gastric cancer tissues, COX-2 expression was correlated significantly with HpaⅡ site demethylation (29/30 vs 5/14, P<0.001 and HhaI site demethylation (28/30 vs 9/14,P<0.05). CONCLUSION: The demethylation of 5' CpG island of gene is necessary for COX-2 expression in human gastric cancer. The expression status of COX-2 may provide theoretical basis for COX-2 targeting gastric cancer treatments.     

Roles of Helicobacter pylori infection and cyclooxygenase-2 expression in gastric carcinogenesis

AIM: Cyclooxygenase (COX)-2 is over expressed in gastrointestinal neoplasm. Helicobacter pylori (H pylori) infection is causally linked to gastric cancer. However, the expression of COX-2 in various stages of H pylori-associated gastric carcinogenesis pathway has not been elucidated. Therefore, the aim of this study was to clarify the role of H pylori induced COX-2 expression during carcinogenesis in the stomach. METHODS: Gastric biopsies from 138 subjects (30 cases of chronic superficial gastritis (CSG), 28 cases of gastric glandular atrophy (GA), 45 cases of gastric mucosal intestinal metaplasia (IM), 12 cases of moderate gastric epithelial dysplasia and 23 cases of gastric cancer) were enrolled. H pylori infection was assessed by a rapid urease test and histological examination (modified Giemsa staining). The expression of COX-1 and COX-2 in human gastric mucosa was detected by immunohistochemical staining. RESULTS: H pylori infection rate was 64.3% in GA and 69.5% in gastric cancer, which was significantly higher than that (36.7%) in CSG (P<0.05). The positive expression rates of COX-2 were 10.0%, 35.7%, 37.8%, 41.7% and 69.5% in CSG, GA, IM, dysplasia and gastric cancer, respectively. From CSG to GA, IM, dysplasia and finally to gastric cancer, expression of COX-2 showed an ascending tendency, whereas COX-1 expression did not change significantly in the gastric mucosa. The level of COX-2 expression in IM and dysplasia was significantly higher in H pylori-positive than in H pylori-negative subjects (P<0.01). CONCLUSION: COX-2 expression induced by H pylori infection is a relatively early event during carcinogenesis in the stomach.     

Increased expression of cyclooxygenase-2 in first-degree relatives of gastric cancer patients

AIM: To study the expression of cydooxygenase-2 (COX-2) in human gastric cancer tissues and their paired adjacent mucosa, as well as mucosa from gastric antrum and corpus of the first-degree relatives of the recruited cancer patients. METHODS: The expression of COX-2 mRNA in 38 patients with gastric cancer and their 29 first-degree relatives and 18 healthy controls was assessed by the real time RT-PCR. The expression of COX-2 protein was determined by Western blot. RESULTS: A marked increase in COX-2 mRNA expression was found in 20 of 37 (54%) cancerous tissues compared to their respective paired normal mucosa (P<0.001). Interestingly, increased COX-2 mRNA expression was also found in mucosa of the corpus (6/29) and antrum (13/29) of their first-degree relatives. Increased COX-2 mRNA expression was more frequently observed in the antrum biopsies from cancer patients than in the antrum biopsies from healthy controls (P<0.05). In addition, 3 of 23 (13%) patients with atrophic mucosa and 6 of 35 (17%) patients with intestinal metaplasia showed increased COX-2 mRNA expression. Furthermore, COX-2 expression increased in H pylori-positive tissues, especially in antrum mucosa. CONCLUSION: Increased COX-2 expression is involved in gastric carcinogenesis, and may be necessary for maintenance of the malignant phenotype and contribute to Helicobacter pylori-associated malignant transformation.     

幽门螺杆菌感染对胃黏膜环氧合酶-2表达的影响

目的评估幽门螺杆菌(Hp)感染对慢性胃炎胃黏膜环氧合酶-2(COX-2)表达的影响.方法与10例正常对照者比较,用免疫组化方法半定量检测46例慢性胃炎患者Hp根除治疗前后胃窦黏膜COX-2蛋白的表达,用悉尼分类标准对胃黏膜炎症、活动性和Hp密度进行半定量测定.结果在胃黏膜表面上皮、腺上皮细胞和固有层间质细胞的胞浆中可见COX-2表达.与正常对照者比较,Hp感染胃黏膜的COX-2平均阳性细胞率明显增加[(18.0±14.1)%比(12.3±4.6)%,P＜0.05)];成功根除Hp后的胃黏膜COX-2平均阳性细胞率明显下降[(20.1±13.1)%比(13.8±5.9)%,P＜0.05)];COX-2表达与慢性炎症计分相关(r=0.78,P＜0.05).结论Hp感染导致胃黏膜COX-2表达增加,提示COX-2在Hp相关性胃炎发生中起作用.     

COX-2与LRP在胃癌组织中的表达及其意义

目的: 观察环氧合酶-2(cyclooxygenase -2,COX-2)及肺耐药蛋白(lung resistance protein,LRP)在胃癌组织中的表达, 探讨COX-2介导胃癌耐药与LRP的关系.方法: 采用免疫组织化学法, 检测63例胃癌标本与30例非胃癌胃组织中COX-2和LRP的表达, 并分析其表达与胃癌的组织学类型、分化程度、淋巴结转移及与患者的年龄、性别的关系.结果: COX-2和LRP在胃癌组织中阳性表达率高于非胃癌胃组织(87.3% vs 53.3%, 66.7% vs43.3%, 均P<0.05). 胃癌组织中COX-2和LRP的表达与患者的年龄、性别及组织的分化程度、浸润深度等无明显关系; COX-2在淋巴结转移患者的阳性表达率明显高于无转移者(100% vs 69.2%, P<0.05), 而LRP的表达与淋巴结转移无明显关系. 在胃癌组织中COX-2与LRP的表达呈正相关( r = 0.033, P<0.05).结论: LRP可能是引起胃癌原发性耐药的耐药蛋白之一; COX-2可能通过影响LRP的表达介导胃癌耐药性的发生.     

胃癌中环氧化酶-2的研究进展

~~胃癌中环氧化酶-2的研究进展@付唆林!200025上海$上海第二医科大学附属瑞金医院消化内科胃癌;;环氧化酶;;进展~~     

利用组织芯片技术研究COX-2在胃癌中的表达及其与血管生成的关系

目的:研究COX-2在胃癌中的表达及其与血管生成的关系,探讨其在胃癌转移中的作用及与胃癌病理生物学行为的关系．方法:采EnVision方法检测胃癌组织芯片中 COX-2的表达,用CD34进行微血管内皮细胞染色,计算微血管密度(MVD),分析其相关性．结果:COX-2在胃癌中的表达明显高于正常胃黏膜(P=0．001)．COX-2的高表达与胃癌的转移(P=0．019)和胃壁浸润深度(0．031)呈正相关,与胃癌的组织病理分型无关(P=0．495), 与Borrmann分型无关(P=0．109)组织MVD (65．49±20．64)明显高于正常胃黏膜组织 (36．21±18．47,P=0．001)．MVD值与胃癌的组织病理分型(P=0．003)和转移有关(P=0．043), 与胃癌胃壁浸润深度(P=0．627)和Borrmann 分型(P=0．634)无明显相关性．COX-2表达阳性组的MVD指数明显高于COX-2表达阴性组 (68．59±19．8 vs 25．82±7．76．P<0．05),COX-2 表达与MVD呈正相关(P=0．001)．结论:组织芯片技术对于快速检测胃癌及其他肿瘤的分子病理学改变是一个强有力的工具．COX-2表达可能通过促进血管形成对胃癌的发生、发展起重要作用,其可作为判断预后和指导治疗的有效指标．     

幽门螺杆菌感染对老年人胃黏膜环氧合酶-2表达的影响及意义

目的:评估幽门螺杆菌(H pylori)感染对老年人胃黏膜COX-2表达的影响及意义.方法:取不同阶段的胃黏膜病变共200例,用速尿素酶试验结合组织学Giemsa染色或14C尿素呼气试验检测胃黏膜H pylori感染状况,应用免疫组织化学检测胃黏膜上皮细胞COX-2的表达.结果:不同组织类型H pylori检出率以胃癌最高,其次为不典型增生(AH)和肠上皮化生(IM).COX-2在慢性浅表性胃炎(CSG)、IM、AH和胃癌中的表达阳性率分别为8%、24%、46%和64%,呈递增趋势,其阳性率胃癌与非癌组织相比差异均有统计学意义(P<0.01).同一类型 H pylori 阳性组COX-2的表达高于H pylori 阴性组,2组比较有显著性差异(P＜0.05).结论:COX-2表达上调与H pylori感染的胃黏膜的癌变有关,可能在癌前病变早期阶段起作用.     

环氧合酶-2在小儿慢性炎症胃黏膜中的表达

目的探讨小儿时期不同炎症胃黏膜环氧合酶也（COX-2）表达特点及可能意义。方法随机抽取正常胃黏膜、普通慢性胃炎、幽门螺杆菌（Hp）相关慢性胃炎、慢性胃炎伴肠上皮化生（无却感染）共110例蜡块重新切片作常规病理学评估，并应用免疫组化法分析胃黏膜COX-2表达。结果COX-2在正常胃黏膜无表达；普通胃炎组9例轻度表达（22．5％）；坳胃炎组27例轻度表达（67．5％），中度表达2例（5．0％）；肠化组轻度表达6例（30．0％）。坳相关胃炎较普通胃炎组及肠化组（均为轻度炎症）COX-2阳性率细显著升高（P=0．000和P=0．002）；普通胃炎组中重度炎症COX-2阳性率较轻度炎症高（P=0．025）。慢性胃炎伴肠化组和普通胃炎组炎症程度无差别（P：0．527），其COX-2阳性表达率一致（P=0．542）。结论小儿胃炎COX-2表达较弱，却感染可诱发COX-2表达，其表达率随炎症程度加重而升高，COX-2表达和肠化无关。小儿早期轻度表达COX-2，其生理意义可能与成人有所不同。     

COX-2及其选择性抑制剂在胃癌中的研究进展

环氧合酶-2(COX-2)是花生四烯酸合成前列腺素的关键限速酶.近年来大量研究表明,COX-2的高表达在胃癌肿瘤细胞进展中发挥着重要作用,其选择性抑制剂能够降低胃癌的发生率.     

Role of cyclooxygenase-2 in gastric cancer development and progression

Although the incidence of gastric cancer has been declining in recent decades,it remains a major public health issue as the second leading cause of cancer death worldwide.In China,gastric cancer is still the main cause of death in patients with malignant tumors.Most patients are diagnosed at an advanced stage and mortality is high.Cyclooxygenase-2(COX-2)is a ratelimiting enzyme in prostanoid synthesis and plays an important role in the development and progression of gastric cancer.The expression of COX-2 in gastric cancer is upregulated and its molecular mechanisms have been investigated.Helicobacter pylori infection,tumor suppressor gene mutation and the activation of nuclear factor-kappa B may be responsible for the elevated expression of COX-2 in gastric cancer.The mechanisms of COX-2 in the development and progression of gastric cancer are probably through promoting the proliferation of gastric cancer cells,while inhibiting apoptosis,assisting angiogenesis and lymphatic metastasis,and participating in cancer invasion and immunosuppression.This review is intended to discuss,comment and summarize recent research progress on the role of COX-2 in gastric cancer development and progression,and elucidate the molecular mechanisms which might be involved in the carcinogenesis.     

环氧化酶-2与胃癌的研究进展

环氧化酶（COX）-2是花生四烯酸合成前列腺素的限速酶,在胃癌高表达,其表达与炎性因子、肿瘤促进子及幽门螺杆菌感染等多种因素有关。COX-2的高表达通过抑制细胞凋亡、促进新生血管的形成及帮助肿瘤细胞逃逸机体免疫监视等多种作用促进肿瘤的发生及发展。COX-2可以降低肿瘤细胞间的黏附性、促进基底膜的降解及新生淋巴管的形成,促进肿瘤的浸润和转移。COX-2有望成为胃癌治疗的新靶点。     

Helicobacter pylori infection,gastrin and cyclooxygenase-2 in gastric carcinogenesis

Gastric cancer is one of the most frequent neoplasms and a main cause of death worldwide, especially in China and Japan. Numerous epidemiological, animal and experimental studies support a positive association between chronic Helicobacter pylori(H. pylori) infec-tion and the development of gastric cancer. However, the exact mechanism whereby H. pylori causes gastric carcinogenesis remains unclear. It has been demon-strated that expression of cyclooxygenase-2(COX-2) is elevated in gastric carcinomas and in their precursor le-sions. In this review, we present the latest clinical and experimental evidence showing the role of gastrin and COX-2 in H. pylori-infected patients and their possible association with gastric cancer risk.     

Constitutive expression and function of cyclooxygenase-2 in murine gastric muscles

BACKGROUND & AIMS: Cyclooxygenase enzymes (COX) generate intermediates in the prostaglandin (PG) cascade. COX-1 is constitutively expressed in many cells, and COX-2 is typically thought to be an inducible isoform. METHODS: We evaluated constitutive expression and function of COX-2 in murine gastric muscles. RESULTS: Immunohistochemistry showed COX-2-like immunoreactivity (COX-2-LI) in myenteric neurons. Half the neurons with COX-2-LI expressed nitric oxide synthase (NOS). COX-2-LI was not observed in smooth muscle cells. Interstitial cells of Cajal within muscle layers (IC-IM) expressed COX-2-LI, suggesting a novel role for IC-IM. Molecular studies verified expression of COX-2 in gastric muscles. Quantitative polymerase chain reaction (PCR) showed equal expression of COX-1 and COX-2 in the antrum. COX-2 was more abundant in fundus. Indomethacin and GR253035X, a COX-2 inhibitor, increased antral phasic contractions and potentiated responses to ACh. Indomethacin, but not GR253035X, increased contractions and potentiated responses in tissues of COX-2 knockout mice. Indomethacin and GR253035X reduced tone in the fundus. CONCLUSIONS: COX-2 is constitutively expressed by IC-IM and neurons in the stomach and at levels similar to COX-1. Prostanoids produced by COX-2 regulate mechanical activities of fundus and antral muscles.     

COX-2在胃溃疡与胃癌的表达及其与幽门螺杆菌的关系

[目的]探讨COX-2在幽门螺杆菌(Hp)感染和非感染胃溃疡与胃癌的表达。[方法]选择胃病患者共285例,分为胃溃疡患者(胃溃疡组)200例(病理分型:肠上皮化生96例和异型增生104例),胃癌患者(胃癌组)85例;以正常胃黏膜者50例为对照组。根据胃镜检查和组织病理学检查受试者胃黏膜中COX-2蛋白的表达,并比较各病理分型及Hp感染与非感染者COX-2蛋白表达的差异。[结果]COX-2蛋白在胃溃疡组的肠上皮化生、异型增生中及胃癌组癌细胞中均有表达,在正常胃黏膜组织中不表达。胃溃疡组和胃癌组的COX-2阳性表达均强于对照组,差异有统计学意义(P0.05);胃癌组的COX-2阳性表达强于胃溃疡组,差异有统计学意义(P0.05);胃溃疡组异型增生者COX-2阳性表达强于肠上皮化生者,差异有统计学意义(P0.05);胃癌组Hp阳性COX-2阳性表达强于胃溃疡组Hp阳性者,差异有统计学意义(P0.05);胃癌组Hp阴性者COX-2阳性表达强于胃溃疡组Hp阴性者,差异有统计学意义(P0.05);胃溃疡组和胃癌组中Hp阳性者COX-2阳性表达均强于Hp阴性者,差异有统计学意义(P0.05)。[结论]Hp感染会促进胃溃疡COX-2的表达,Hp感染和COX-2过度表达会使胃溃疡患者癌变的概率大大增加。     

Overexpression of cyclooxygenase-2 and tumor angiogenesis in human gastric cancer

BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2) protein is overexpressed in various cancers, including esophageal, gastric, colon, and pancreatic. To better comprehend the role of COX-2 in gastric cancer, especially with regard to angiogenesis, we investigated COX-2 and vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) in 108 patients with gastric cancer. METHODOLOGY: We used immunohistochemical analysis of formalin-fixed tissues of gastric cancer. RESULTS: Expression of COX-2 showed diffuse staining in the cytoplasm of tumor cells, however, no staining in normal epithelial cells. Of the 108 tumors examined, 71 (65%) were positive for COX-2 expression, the VEGF-positive cases numbered 43 of 108 cases (39.8%). The intensity of COX-2 expression did not correlate with any clinicopathological characteristics. The positive rate of VEGF expression in COX-2-positive cases was significantly higher than in COX-2-negative ones (47.9% vs. 24.3%, P<0.05). MVD in COX-2-positive cases was significantly higher than in COX-2-negative ones (22.0+/-7.8 vs. 18.5+/-7.5/1 mm2; P<0.05). CONCLUSIONS: Our study provides evidence that COX-2 is closely related with angiogenesis.     

特异性环氧合酶-2抑制剂预防胃癌的实验研究

目的 探讨特异性环氧合酶(COX)-2抑制剂塞来昔布(Celecoxib)对化学致癌剂(N-甲基-N′-硝基-亚硝基胍，MNNG)诱导的胃癌发生的影响。方法 86只二级雄性Wistar大鼠分为A、B、C、D、E、F共6组。A组(5只)：自由饮用蒸馏水不作特殊处理；B组(16只)：仅饮用含MNNG 100μg/ml的蒸馏水；C组(16只)：每天给予吲哚美辛3mg／kg；D组(17只)：每天给予塞来昔布5mg／kg；E组(16只)：每天给予塞来昔布10mg／kg；F组(16只)：每天给予塞来昔布20mg／kg。B～F组动物给予10％氯化钠(实验初6周)和饮水中加用MNNG(10μg／ml)，以诱导胃癌，持续40周，第48周时处死动物。观察、比较各组动物大体及组织学变化。结果 86只大鼠实验期间自然死亡26只(30％)，余60只完成实验研究。A、B、C、D、E、F组动物胃癌发生率分别为0％(0／5)、75．0％(12／16)、68．8％(11／16)、70．6％(12／17)、18．8％(3／16)和31．3％(5／16)。各组动物胃癌发生率(P=0．002)、多发数目(P=0．001)、肿瘤体积(P=0．009)差异有显著性。与B组相比，E组胃癌发生率(P=0．004)、多发数目(P=0．006)和肿瘤体积(P=0．02)显著降低。C组与B组相比差异无显著性。结论本研究提示塞来昔布对MNNG诱导的大鼠胃癌有预防作用，而吲哚美辛未见此效果。