Up-regulated claudin 7 expression in intestinal-type gastric carcinoma

The disruption of tight junction protein expression in cancer might account for invasiveness, loss of cohesion, and lack of differentiation. Our cDNA array data indicated that claudin 7 was up-regulated in gastric carcinoma. We investigated the expression patterns and clinical implications of claudin 7 in gastric cancer. By immunohistochemical staining and Western blot, claudin 7 was significantly more often expressed in intestinal metaplasia, adenoma and cancer than in normal gastric epithelium. Twenty-seven (47.4%) of 57 normal gastric epithelium samples did not express claudin 7, but 50 (86.2%) of 58 intestinal metaplasia, 11 (91.7%) of 12 adenoma tissues, and 129 (82.7%) of 156 cancer samples did. Claudin 7 was more often unexpressed in diffuse type gastric cancer than in intestinal type. Only 13 (11.2%) of 116 intestinal type samples did not express claudin 7, but 14 (41.2%) of 34 diffuse type samples showed no expression. Compared to normal gastric epithelium, intestinal type gastric cancer significantly more often expressed claudin 7, but diffuse type did not. The expression pattern of claudin 7 did not change as cancer progressed. In this study we show that claudin 7 expression changed with the gastric carcinogenic process and that this is implicated in cancer characteristics.     

Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia

Loss of Sonic Hedgehog (Shh) and aberrant CDX2 expression are early changes correlating with the presence of intestinal metaplasia that occur in the gastric mucosa prior to neoplastic transformation. The aim of this study was to compare the improvement in corpus gastritis with Shh and CDX2 expression after H. pylori eradication between subjects at high risk for gastric cancer and controls. The usefulness of serum pepsinogen levels as a predictor of resolved corpus gastritis was also examined. Seventy patients with endoscopic resection for early gastric cancer and 30 controls were studied. Expression of Shh and CDX2 were evaluated by immunostaining. Serum levels of pepsinogen I before eradication in the patients scored as having improvement of corpus atrophy were significantly higher than in the patients without improvement (<0.01). Residual inflammation at the corpus lesser curve was more frequently detected in the cancer group than in the controls (OR 4.6 95% C.I. 1.6-13.5) and in the mucosa with incomplete intestinal metaplasia rather than in those without incomplete intestinal metaplasia (OR 7.6 95% C.I. 2.4-24.3). Atrophy, expression of Shh and CDX2 at the corpus lesser curve significantly improved in mucosa without incomplete intestinal metaplasia (p < 0.01), but not in mucosa with incomplete intestinal metaplasia. In conclusion, H. pylori eradication prior to development of incomplete intestinal metaplasia improves corpus gastritis and may prevent gastric cancer. Pepsinogen I may be a useful marker in patients with a residual higher risk of gastric cancer after H. pylori eradication.     

De-regulation of the sonic hedgehog pathway in the InsGas mouse model of gastric carcinogenesis

This study investigated sonic hedgehog (Shh) signalling in gastric metaplasia in the insulin-gastrin (InsGas) hypergastrinaemic mouse +/- Helicobacter felis (H. felis) infection. Sonic hedgehog gene and protein expression was reduced in pre-metaplastic lesions from non-infected mice (90% gene reduction, P<0.01) compared to normal mucosa. Sonic hedgehog was reactivated in gastric metaplasia of H. felis-infected mice (3.5-fold increase, P<0.01) compared to pre-metaplastic lesions. Additionally, the Shh target gene, glioma-associated oncogene (Gli)-1, was significantly reduced in the gastric glands of InsGas mice (75% reduction, P<0.05) and reactivated with H. felis infection (P<0.05, base of glands, P<0.01 stroma of metaplastic glands). The ability of H. felis to activate the Shh pathway was investigated by measuring the effect of target cytokine, interleukin-8 (IL-8), on Shh expression in AGS and MGLVA1 cells, which was shown to induce Shh expression at physiological concentrations. H. felis induced the expression of NF-kappaB in inflammatory infiltrates in vivo, and the expression of the IL-8 mouse homologue, protein KC, in inflammatory infiltrates and metaplastic lesions. Sonic hedgehog pathway reactivation was paralleled with an increase in proliferation of metaplastic lesions (15.75 vs 4.39% in infected vs non-infected mice, respectively, P<0.001). Furthermore, Shh overexpression increased the growth rate of the gastric cancer cell line, AGS. The antiapoptotic protein, bcl-2, was expressed in the stroma of infected mice, along with a second Shh target gene, patched-1 (P=0.0001, stroma of metaplastic gland). This study provides evidence suggesting reactivation of Shh signalling from pre-metaplastic to advanced metaplastic lesions of the stomach and outlines the importance of the Shh pathway as a potential chemoprophylactic target for gastric carcinogenesis.     

Differential expression of peroxisome proliferator-activated receptor in histologically different human gastric cancer tissues

Gastric cancer cell lines express peroxisome proliferator-activated receptor gamma (PPARgamma), and treatment with PPARgamma ligands suppresses growth of subgroup of these cell lines. However, expression and subcellular distribution of PPARgamma in human gastric cancer tissues is still unknown. Therefore, expression and subcellular localization of PPARgamma were examined among different histological types of gastric cancer tissues. Immunohistochemical staining for PPARgamma was performed using biopsy specimens of human gastric cancer of various histological types, gastric adenomas, and intestinal metaplasia. All samples of intestinal metaplasia and most samples of gastric tumors, except for signet ring cell carcinoma, expressed PPARgamma in the epithelial cells. Most samples of signet ring cell cancer lacked PPARgamma expression. All samples of intestinal metaplasia expressed PPARgamma only in the cytosol. For adenoma, 90% was positive for PPARgamma in cytosol, and 40% was positive in nuclei, for well-differentiated adenocarcinoma, 80% was positive in cytosol, and 20% was positive in nuclei. For moderately differentiated adenocarcinomas, 70% was positive for cytosol, and 80% was positive for nuclei; for poorly differentiated adenocarcinoma, 30% was positive in cytosol, and 70% was positive in nuclei. The frequency of samples with positive cytosolic staining decreased as the differentiation stage turned from intestinal metaplasia to adenoma, well-, moderately-, and poorly-differentiated cancers. Simultaneously, there was a tendency toward an increased frequency of samples with positive nuclear PPARgamma staining as the differentiation stage transformed from intestinal metaplasia to poorly-differentiated cancer. There was a striking difference in subcellular localization according to the differentiation levels of gastric dysplastic cells. The findings also supported an intestinal metaplasia-adenoma-well-differentiated gastric cancer sequence, and signet ring cell cancer was suggested to be of a different lineage from other types of gastric cancers.     

音猬因子、Ptch1基因在胃癌中的表达及临床意义

目的:研究胃癌组织中音猬因子（Shh）、Patched1(Ptch1)基因的表达及意义。方法:采用反转录-聚合酶链反应(RT-PCR)和Westem blot检测98例胃癌组织和配对的癌旁组织中Shh、Ptch1 mRNA和蛋白的表达情况。结果:RT-PCR检测结果显示,Shh、Ptch1 mRNA在胃癌中相对表达量分别为0.687±0.057、0.594±0.046,在胃癌旁组织中分别为0.314±0.025、0.293±0.074（P＜0.05）。Western blot检测结果显示,Shh、Ptch1蛋白在胃癌中的相对表达量分别为0.525±0.057、0.481±0.046,在胃癌旁组织中分别为0.236±0.025、0.215±0.074。胃癌组织Shh、Ptch1 mRNA和蛋白平均表达水平高于癌旁组织,差异有统计学意义（P＜0.05）;Shh、Ptch1 mRNA和蛋白表达水平与胃癌的分化程度、TNM分期、浸润深度和淋巴结转移明显相关（P＜0.05）,与患者年龄、性别和肿瘤直径无明显相关（P＞0.05）。结论:胃癌组织中Shh、Ptch1蛋白呈高表达,Shh、Ptch1蛋白的高表达可能与胃癌的发生及发展有关。     

胃癌组织中Sonic Hedgehog和VEGF表达及临床意义的研究

目的:探讨胃腺癌中Sonic Hedge-hog(Shh)和VEGF的表达及临床意义。方法:应用免疫组化法检测45例胃癌组织及15例癌旁胃黏膜组织中Shh和VEGF的表达。结果:Shh在胃癌组织中阳性表达率为66.7%,在中、低分化胃癌中的表达高于高分化胃癌中的表达,与组织分化程度相关,P<0.01,在癌旁胃黏膜组织中Shh表达为阴性或弱阳性(15.3%);VEGF在胃癌组织中的阳性表达率(71.1%)显著高于癌旁胃黏膜组织中的阳性表达率(26.7%),P<0.01,与肿瘤分化程度、淋巴结转移呈正相关,P<0.05。Shh和VEGF在胃癌组织中的表达存在相关性(0.01相似文献   

Expression of placental alkaline phosphatase in gastric and colorectal cancers. An immunohistochemical study using the prepared monoclonal antibody

The authors developed monoclonal antibodies (MoAb) against human placental alkaline phosphatase (PLAP). Four specific MoAb reacting only with PLAP and two nonspecific MoAb reacting equally with isozymes of alkaline phosphatase (hepatic, intestinal, and placental) were obtained. Immunohistochemical staining with the specific MoAb showed that the cell membrane and cytoplasm of cancer cells were stained in gastric and colorectal carcinoma. The incidence of PLAP positivity was 23% (25 of 107) of all gastric carcinomas. Among gastric carcinomas, the 42% (13 of 31) positivity of highly differentiated carcinoma (papillary adenocarcinoma and well-differentiated tubular adenocarcinoma) was a significantly higher rate than that found in poorly differentiated carcinoma (poorly differentiated adenocarcinoma and signet-ring cell carcinoma, five of 41, 12%). The incidence of PLAP positivity was 11% (four of 35) in colorectal carcinoma. In contrast, gastric adenoma, intestinal metaplasia, and noncancerous tissue adjacent to cancer did not show staining. These results indicated that expression of PLAP was apt to occur in more highly differentiated gastric carcinoma and was highly specific for carcinoma in the gastrointestinal tract, although its incidence was not high.     

Antigen MG7 in gastric cancer and gastric precancerous lesions

Earlydetectionandearlydiagnosisofgastriccancerareessentialtodecreasethemortalityandincreasesurvivalrateofgastriccancer.TheZhuangheregioninLiaoningProvinceisahighriskareaofgastriccancerandanimportantresearchbaseforgastriccancerpreventionandtreatmentinChina[1].AlargescalescreeningofgastriccancerinthisareawascarriedoutbytheCancerInstituteofChinaMedicalUniversitypreviously.Inthepresentstudy,thegastricmucosasamplesfromthescreeningwereusedtoinvestigatethedynamicexpressionofgastriccancer-associat…     

PTCH在胃黏膜肠上皮化生、不典型增生和胃癌中的表达

目的 探讨Hedgehog信号传导通路的PTCH与胃癌的分化程度、侵袭、临床分期及其发生、发展的关系.方法 采用免疫组织化学法(ABC法)和RT-PCR法检测42份胃癌组织、20份肠上皮化生组织、15份不典型增生组织、7份正常胃组织中PTCH的表达.结果 PTCH基因在正常胃组织、肠上皮化生组织、不典型增生组织、胃癌组织中的表达分别为0、10.0%、40.0%、78.6%,差异有统计学意义(P＜0.05),在正常组织中不表达,在肠上皮化生组织中轻度表达,不典型增生组织以中度表达为主,而胃癌组织多呈过度表达.结论 PTCH与胃癌的分化程度、侵袭、临床分期有关,其表达对判断预后有一定价值.PTCH可能参与了胃癌的发生.     

Late reactivation of sonic hedgehog by Helicobacter pylori results in population of gastric epithelial cells that are resistant to apoptosis: Implication for gastric carcinogenesis

As much as that a disturbance of tissue homeostasis through dysregulated apoptosis is generally associated with carcinogenesis, gastric carcinogenesis after Helicobacter pylori infection could be the accumulated consequence of imbalances between apoptosis and proliferation. Since sonic hedgehog (Shh) has been reported to play versatile roles in various tumorigenesis, we hypothesized that late reactivation of sonic hedgehog by H. pylori infection results in population of gastric epithelial cells that are resistant to apoptosis. The Resistant Clones against H. pylori-induced Apoptosis (RCHA) were established and maintained up to 19th cell passages, during which the serial changes of Shh expression were measured. Apoptosis was measured in N-Shh over-expressed stable cell lines and compared with parent cell line after either infected with H. pylori or treated with cyclopamine. For clinical relevance, the expressions of Shh were compared in tissues from gastric adenoma or adenocarcinoma according to H. pylori infection. Longer passages of RCHA after H. pylori infection, the higher expressions of Shh, suggesting RCHA was associated with the reactivation of Shh. Significant decrement in subG1 phase of cell cycle and attenuated executions of apoptosis after H. pylori infection in cells of Shh overexpression, whereas either Shh siRNA or cyclopamine increased the H. pylori-induced cytotoxicity and significantly abrogated anti-apoptotic actions imposed by Shh. Significantly higher expressions of Shh were seen in H. pylori-associated gastric cancers than H. pylori-not associated gastric cancer. Late reactivation of sonic hedgehog by H. pylori infection results in population of gastric epithelial cells that are resistant to apoptosis and imposes proliferative changes under the background of atrophic gastritis, providing the carcinogenic basis.     

Loss of pS2 Protein Expression Is an Early Event of Intestinal-type Gastric Cancer

To investigate the prevalence of pS2 expression in gastric cancer with respect to tumor histopathology, intestinal metaplasia and Helicobacter pylori (H. pylori ) infection, pathologic specimens of 91 patients with gastric cancer were immunostained for pS2. Such immunoreactivity was correlated with the status of H. pylori infection, tumor staging, histology, subtyping, and associated intestinal metaplasia. Positive pS2 staining was seen throughout all non-neoplastic epithelia, and in all 9 patients with the complete type of intestinal metaplasia. In contrast, 21 of 45 incomplete type of intestinal metaplasia had negative pS2 staining ( P <0.001), and 54 out of 91 tumors (59.3%) showed loss of pS2 expression in the cancer tissues proper. There was no correlation of pS2 expression with age, gender, depth of invasion, duodenal involvement, lymph node metastasis, venous invasion or H. pylori infection. Negative pS2 staining was significantly higher in the intestinal (74.5%) and Borrmann type I, II, III (64.2%) tumors than the diffuse (43.2%, P <0.005) and Borrmann type IV (20%, P <0.05) tumors. Our results indicate that loss of pS2 expression may occur as an early event in the malignant transformation process of intestinal-type tumors.     

FXR和CDX2在胃黏膜肠化生及胃癌中的表达及意义

目的:探讨法尼酯衍生物X受体(farnesoid X receptor,FXR)和尾型同源盒2(caudal type homeobox 2,CDX2)在胃黏膜肠化生(intestinal metaplasia,IM)及胃癌中的表达和意义。方法:采用免疫组织化学染色法检测FXR和CDX2在30例慢性胃炎、50例IM、60例胃癌组织中的表达。利用卡方检验比较各组间FXR和CDX2的表达差异,并分析其与肠化生和胃癌患者临床病理参数的关系。利用Spearman秩相关检验分析FXR和CDX2表达的相关性。结果:IM和胃癌组织中FXR的高表达率分别为58.0%和38.3%,较慢性胃炎组织(13.3%)均显著增高（P＜0.05）。与IM组织相比,胃癌组织中FXR表达显著下降（P=0.040）。FXR高表达与IM患者肠化生程度较重（中重度）相关（P=0.025）。FXR高表达与胃癌患者分化较好（中高分化）相关（P=0.003）。IM和胃癌组织中CDX2的高表达率分别为46.0%和26.7%,较慢性胃炎组织(6.7%)均显著增高（P＜0.05）。与IM组织相比,胃癌组织中CDX2表达显著下降（P=0.035）。CDX2高表达与IM患者肠化生程度较重（中重度）相关（P=0.004）。CDX2高表达与胃癌患者分化较好（中高分化）相关（P<0.001）。FXR和CDX2表达在慢性胃炎、IM、胃癌组织中均显著正相关（P<0.001）。结论:FXR和CDX2在IM和胃癌组织中表达均上调且显著正相关,可能共同参与了IM和胃癌的发生发展。     

热休克蛋白70在人胃癌中呈过度表达

目的：研究热休克蛋白７０（ＨＳＰ－７０）在人胃癌组织中的表达。方法：应用抗人ＨＳＰ７０单克隆抗体对１９０例手术及胃镜活检胃癌及非癌胃粘膜病变石蜡标本,以免疫组织化学ＡＢＣ法检测ＨＳＰ７０的表达。结果：ＨＳＰ７０在胃癌、慢性浅表性胃炎、肠上皮化生及不典型增生组织中的阳性率分别为７３％、３２．５％、６６％及７２％;地表达率分别为５６％、５．８％、２９．２％及３３．３３％。ＨＳＰ７０在肠上皮化生、不典型     

胃癌组织中Sonic Hedgehog表达及其与NF-kappaB的关系研究

目的探讨Hedgehog在胃癌及其癌前病变中的表达及与NF-kappaB的关系。方法选择50例萎缩性胃炎、46例肠化生和57例胃癌患者的胃黏膜内镜活检样本,同时选择30例正常人作为对照;分为萎缩性胃炎组、肠化生组、胃癌组和正常黏膜组。通过病理学检测患者Hpylori感染状况。免疫组化法检测Hedgehog和NF-kappaB在不同阶段胃癌组织中的表达差异。流式细胞仪分析各组胃黏膜细胞的周期分布和凋亡率。Western blot检测Hedgehog表达。结果在胃癌的发展过程中,胃黏膜组织中Hedgehog表达水平先降低后升高。NF-kappaB表达水平在正常胃组织、萎缩性胃炎和肠化生组织中无明显变化,但在胃癌组织中表达显著增强。与正常胃黏膜组织比较,萎缩性胃炎、肠化生和胃癌组织中的S期细胞比例更高。细胞凋亡率萎缩性胃炎组和肠化生组较高,而胃癌组较低。抑制NF-kappaB后,Hedgehog蛋白在胃癌组织中的表达降低。结论在胃癌的发展过程中,Hedgehog蛋白表达水平先降低后升高。H pylori感染可能通过激活NF-kappaB,继而增强Hedgehog表达,同时赋予胃癌细胞凋亡抵抗。     

Caveolin-1在胃癌组织中的表达及临床生物学意义

背景与目的:Caveolin-1作为候选抑癌基因,在多种肿瘤均有异常表达。本研究探讨Caveolin-1在非癌胃粘膜、肠上皮化生、异型增生和胃癌组织以及胃癌细胞系MGC803和BGC823的表达特点。方法:采用冰冻组织微阵列的免疫组织化学(immunohistochemistry,IHC)染色,在完全相同的实验条件下检测56例胃癌及29例非癌粘膜、11例肠上皮化生、7例异型增生组织中Caveolin-1的表达状况,及其与胃癌的临床病理分期、淋巴结转移、Lauren分型及组织学分型的关系。Westernblot和RT-PCR法检测胃癌及相应癌旁组织与MGC-803和BGC-823细胞中Caveolin-1蛋白和RNA的表达情况。结果:免疫组化结果显示,Caveolin-1在非癌胃粘膜、肠上皮化生、异型增生和胃癌中的阳性率分别为86.2%(25/29)、81.8%(9/11)、57.1%(4/7)、17.9%(10/56);胃癌与其它各组间的阳性率有显著性差异(P<0.05)。进展期胃癌的Caveolin-1阳性率(16.0%)低于早期胃癌(33.3%),但无统计学意义(P>0.05)。弥漫型胃癌的阳性率(7.0%)明显低于肠型胃癌(26.9%,P<0.05)。有淋巴结转移的胃癌Caveolin-1阳性率(9.7%)低于无淋巴结转移(31.8%,P<0.05)。Westernblot及RT-PCR结果显示,胃癌组织和相应非癌胃粘膜组织中Caveolin-1的表达无显著性差异,但MGC-803和BGC-823细胞中Caveolin-1表达     

The relationship between stomach cancer and intestinal metaplasia of the gastric mucosa and food intake

The natural history of intestinal metaplasia of gastric mucosa was studied in 414 rural inhabitants; 213 males and 201 females, from Chokai Village in Akita Prefecture in the northeast part of Japan's main island of Honshu. The subjects were examined by a mobile gastrointestinal unit and were biopsied at eight standard points of the gastric mucosa. The specimens were examined histologically, and were divided into 4 grades. The metaplasia index (MI) was adopted as a quantitative expression of the severity of intestinal metaplasia of the gastric mucosa. The MI of the three areas of the village were compared with the different incidences of stomach cancer. The following results were obtained: in gastric mucosa. The average values of the MI among the male population were highest at the high-risk area, low at the low-risk area and intermediate at the moderate-risk area of gastric cancer. Whereas, the values among females showed no differences in these three areas. The risks for stomach cancer also were almost equal. These phenomena would show a very close relationship between intestinal metaplasia and the incidence of stomach cancer. There was a positive correlation (p less than 0.01) between MI and the detection rates of stomach cancer by a mass screening examination in the areas. Study of food intake and especially the salt consumption among the three areas showed a close relationship with intestinal metaplasia. Certain foods seemed to relate to intestinal metaplasia and eventually to stomach cancer. The conclusion was drawn that the development of intestinal metaplasia could be prevented by the improvement of environmental factors especially by that of food intake. Thus, the reduction in the incidence of stomach cancer also would be possible.