用组织芯片技术研究环氧合酶-2在不同亚型胃黏膜肠化生及胃癌中的表达

目的研究环氧合酶-2(cyclooxygenase-2,COX-2)蛋白在不同亚型胃黏膜肠化生(intestinal metaplasia,IM)及胃癌中的表达,探讨其做为预测IM恶变趋势指标的可能性,同时明确COX-2表达与胃癌发生间的关系。方法选择40例慢性萎缩性胃炎(chronic、atrophic gastritis,CAG)伴IM、40例胃癌及相应癌旁组织,构建组织芯片。分别用高铁二铵/爱先蓝(HID/AB)及HE染色对IM及胃癌进行分型,免疫组化检测不同亚型IM及胃癌中COX-2蛋白的表达。结果COX-2蛋白表达阳性率在CAG伴IM灶、癌旁IM灶和肠型胃癌中分别为45.65%、59.38%和77.27%,显著高于弥漫型胃癌(16.67%,P分别<0.05、0.005和0.005),表达强度在CAG伴IM灶→癌旁IM灶→肠型胃癌顺序中呈逐渐升高趋势(P<0.005)。Ⅲ型IM中COX-2表达阳性率显著高于Ⅰ型、Ⅱ型IM(P分别<0.005、0.05),从Ⅰ型、Ⅱ型到Ⅲ型,COX-2表达强度也呈逐渐升高趋势(P<0.005)。结论随着IM愈倾向于恶性,COX-2表达水平也逐渐增高,有可能成为预测IM恶变趋势的有用指标。COX-2表达主要与肠型胃癌的发生有关,但在弥漫型胃癌的发生中可能也有一定作用。     

用组织芯片技术研究环氧合酶-2在不同亚型胃黏膜肠化生及胃癌中的表达(英文)

目的研究环氧合酶-2(cyclooxygenase-2,COX-2)蛋白在不同亚型胃黏膜肠化生(intestinal metaplasia,IM)及胃癌中的表达,探讨其做为预测 IM 恶变趋势指标的可能性,同时明确 COX-2表达与胃癌发生间的关系。方法选择40例慢性萎缩性胃炎(chronic atrophic gastritis,CAG)伴 IM、40例胃癌及相应癌旁组织,构建组织芯片。分别用高铁二铵/爱先蓝(HID/AB)及 HE 染色对 IM 及胃癌进行分型,免疫组化检测不同亚型 IM 及胃癌中 COX-2蛋白的表达。结果 COX-2蛋白表达阳性率在 CAG 伴 IM 灶、癌旁 IM 灶和肠型胃癌中分别为45.65%、59.38%和77.27%,显著高于弥漫型胃癌(16.67%,P分别<0.05、0.005和0.005),表达强度在 CAG 伴 IM 灶→癌旁 IM 灶→肠型胃癌顺序中呈逐渐升高趋势(P<0.005)。Ⅲ型 IM 中 COX-2表达阳性率显著高于Ⅰ型、Ⅱ型 IM(P 分别<0.005、0.05),从Ⅰ型、Ⅱ型到Ⅲ型,COX-2表达强度也呈逐渐升高趋势(P<0.005)。结论随着 IM 愈倾向于恶性,COX-2表达水平也逐渐增高,有可能成为预测 IM 恶变趋势的有片j指标。COX-2表达主要与肠型胃癌的发生有关,但在弥漫型胃癌的发生中可能也有一定作用。     

Outcome of Intestinal Metaplasia in Gastric Biopsy of Patients with Dyspepsia in Guilan Province,North Iran

Background: It is generally accepted that gastric carcinomas are preceded by a sequential multistage processthat includes chronic gastritis, gastric atrophy, usually with intestinal metaplasia (IM), and dysplasia. This seriesof changes in gastric carcinogenesis is often initiated by Helicobacter pylori (H pylori) infection. The aim of thepresent study was determination of gastric histopathologic changes in IM patients after at least one year in Guilanprovince, Iran. Materials and Methods: This case-series study was conducted in Guilan Gastrointestinal and LiverDisease Research Center (GLDRC) during 2010 to 2011. Gastric biopsy was performed for all 71 known cases ofIM and precanceric lesions including gastric atrophy, IM, dysplasia and H pylori infection were determined afterat least one year. Results: Of the total of 71 patients with established IM who were enrolled, 50 had complete-typeIM and 21 had incomplete-type IM. Fifty two people had H pylori infection. H pylori eradication was achievedin 39 patients (75%). Secondary pathology findings of patients with IM were complete metaplasia (39.4%),incomplete metaplasia (32.4%), dysplasia (23.9%) and other precanceric lesions (4.2%). Dysplasia (20%vs 33%)occurred in patients who had complete and incomplete IM at baseline respectively (p>0.05). Age, gender, familyhistory of gastric cancer(GC); smoking habits and NSAIDs use were not associated with gastric premalignantlesions in initial and secondary pathologies (p>0.05). The difference became statistically significant between Hpylori infection in patients with more than 3 years diagnostic intervals (p<0.05). Statistical difference betweeneradicators and non-eradicators was not significant. Conclusions: We found that incomplete IM increased therisk of subsequent dysplasia in this study.     

慢性萎缩性胃炎伴肠化生与胃癌ras基因表达的比较

目的：探讨胃癌发生发展不同阶段癌基因表达特点并予以定量分析，对阐明胃癌发生发展机理及早期诊断胃癌具有重要意义。方法：应用ras基因产物共有多肽序列单克隆抗体PAP免疫组化对照研究了13例慢性萎缩性胃炎伴肠化生（大肠型），32例胃窦癌及15例正常胃窦粘膜ras基因表达特点。结果：慢性萎缩性胃炎伴肠化生粘膜ras基因产物免疫反应阳性细胞形态较规则，呈卵圆形或低柱状，免疫反应强度及阳性细胞数量均较胃癌增强（多）（P均＜0．05）阳性细胞成片分布肠化粘膜下部及基底部，不穿越基底层；胃癌中免疫反应阳性细胞形态不规则，核分裂相明显，成团或散在分布，免疫反应强弱不等，呈异质性表达。正常胃窦粘膜可见谈棕黄色单个分布的ras产物阳性细胞。结论：ras基因在胃癌前病变慢性萎缩性胃炎伴肠化生中已激活，对ras产物精确定量分析有助于胃癌前病变的诊断。     

Quantitation of Gastric Intestinal Metaplasia by Morphometry in Japanese Patients

With the aid of an image processor, the length of the intestinal metaplasia (IM) was recorded in 33 gastrectomy specimens (23 with early gastric cancer and 10 with gastric peptic ulcer). A total of 1917 sections were analyzed. The length of the areas with IM and the total length of the muscularis mucosa were measured in individual sections. The resulting ratio (length of IM/length of muscularis mucosa) was noted as the intestinal metaplasia index (IMI), as an expression of the extension of IM in the specimens. The IMI was influenced by the age of the patient and by the histologic type of the tumor: a higher IMI was found among older patients and among patients with adenocarcinoma of intestinal type. A comparison with a similar study done in gastrectomy specimens from Swedish patients indicates that despite the latter group being older, and the tumors being more advanced, the IM was much more extended in the gastric mucosa of the Japanese patients with gastric adenocarcinomas of intestinal type. From the results it is suggested that extended IM in the gastric mucosa may have some bearing on the histogenesis of gastric carcinomas, particularly adenocarcinomas of intestinal type.     

胃粘膜肠化与胃癌关系的粘液组织化学研究

本文应用粘液组织化学技术，对117例胄癌、62例慢性胃炎伴（肠化生）组织的粘液分泌进行观察。根据所含粘液不同，将胄癌分为肠型及胃型，将畅化分为大肠型及小肠型。肠型胃癌的肠化检出率显著高于胃型胃癌（P＜0．01）。大肠型肠化在肠型胃癌旁肠化检出率显著高于在胄型胄癌旁肠化及慢性胃炎伴肠化的检出率（P＜0．01）。肠型胃癌的发生与胄粘膜肠化，特别与大肠型肠化关系密切。因此，加强对大肠型肠化的密切随访．有利于胃癌的早期发现。     

用组织芯片技术研究环氧合酶-2在不同亚型胃粘膜肠化生及胃癌中的表达

目的:研究环氧合酶-2(cyclooxygenase-2,COX-2)在不同亚型胃粘膜肠化生(intestinal metaplasia,IM)及胃癌中的表达,探讨其预测IM恶变趋势的可能性,同时探讨COX-2表达与胃癌发生间的关系.方法:选择40例慢性萎缩性胃炎(chronic atrophic gastritis,CAG)伴IM、40例胃癌及相应癌旁组织,构建组织芯片.分别用高铁二铵/爱先蓝(HID/AB)及HE染色对IM及胃癌进行分型,然后用免疫组化检测不同亚型IM及胃癌中COX-2蛋白的表达.结果:COX-2表达阳性率在CAG伴IM灶、癌旁IM灶、肠型胃癌中分别为60.87%、75.00%和86.36%,三者间无显著性差异,但表达强度在CAG伴IM灶→癌旁IM灶→肠型胃癌顺序中呈逐渐升高趋势(P＜0.005).肠型胃癌中COX-2表达阳性率及强度均显著高于弥漫型胃癌(P＜0.005).Ⅲ型IM中COX-2表达阳性率显著高于Ⅰ、Ⅱ型IM(P＜0.05),从Ⅰ型、Ⅱ型到Ⅲ型,COX-2表达强度也呈逐渐升高趋势(P＜0.005).结论:随着IM愈倾向于恶性,COX-2表达水平也逐渐增高,其有可能成为预测IM恶变趋势的有用指标.COX-2表达主要与肠型胃癌的发生有关,但在弥漫型胃癌的发生中可能也有一定作用.     

Frequency of Atypical Mitosis in Intestinal Metaplasia of the Gastric Mucosa in Japanese Patients

The morphologic characteristics of the mitotic figures present in intestinal metaplasia (IM) of the gastric mucosa were investigated in 70 concecutive gastrectomy specimens from Japanese nationals. The specimens contained, in addition, early gastric cancer of intestinal type (n=44) or of diffuse type (n=22). The remaining 4 were recorded as mixed. One hundred or more consecutive mitoses/specimens were studied by high-power microscopy in hematoxylin and eosin-stained preparations (at × 1000). A total of 7259 mitoses were recorded (mean 103.7 mitoses/case). Of these, 1089 mitoses (i.e. 19.1%) were considered as atypical according to a previous classification. The percentage of atypical mitoses was found to be unrelated to the gender, to the increasing age of the patients, to the histologic type of the adenocarcinoma contained in the specimens, or to the anatomic site (e.g. corpus or antrum or tumor proximity). Comparative studies were done with gastrectomy specimens from Swedish nationals (a population with a 4-times-lower incidence of gastric carcinoma than the Japanese). The results showed a much lower frequency of mitotic figures/specimen and only occasional atypical mitosis. Since atypical mitosis has so far been reported only for neoplastic lesions in the gastrointestinal tract, it is suggested that IM with atypical mitosis may be a genuine precancerous lesion in the gastric mucosa in Japanese subjects.     

实验性胃粘膜肠上皮化生组织发生的研究

本文首次报道应用小剂量ＭＮＮＧ和雷尼替丁诱发了Ｗｉｓｔａｒ鼠实验性胃粘膜肠化生，应用该模型对肠化的发生、发展过程进行动态观察。肠化最早出现于实验第９周，在第１２周以前，化生只见于腺颈部；第１４、１６周的标本上可见肠化生自腺颈部向上或向下延伸；第１８、２０周及以后的标本上，可见到胃粘膜不同部位的肠化生，尤以胃粘膜下１／３最为显著。结果说明肠化生起源于胃粘膜腺颈部增殖细胞区，之后可向粘膜表面或腺底部发展，似乎以后者为主。     

胃癌分子机制的研究进展

研究表明胃癌干细胞以及T细胞、树突状细胞、一些转录因子和细胞因子、非编码RNA等异常都可能会导致胃癌的发生。全文对胃癌发生发展的细胞生物学和分子机制的研究进展进行综述。     

Prognostic Significance of p27 and Survivin in H. pylori Gastritis and Gastric Cancer

Objective: to assess expression of p27 and survivin in chronic gastritis with/without H. pylori ± intestinal metaplasia (IM) and in intestinal-type gastric cancer (IGC). Materials and Methods: Immunohistochemical staining for p27 and survivin on paraffin-embedded sections of 20 chronic gastritis, 20 H. pylori gastritis, 15 H. pylori gastritis with IM, 50 IGC, and 10 controls. Positivity (number of positive cases) and expression (mean percentage of positive gastric cells) for both proteins were evaluated. Results: P27 positivity and expression decreased from control to chronic gastritis to H. pylori gastritis to H. pylori gastritis with IM. In IGC, p27 positivity and expression were lower than controls and chronic gastritis but higher than H. pylori gastritis ±IM. High grade and advanced stage IGCs have insignificantly lower p27 positivity and expression than low grade and early stage IGCs. By contrast, survivin positivity and expression increased from chronic gastritis to H. pylori gastritis to H. pylori gastritis with IM to IGCs. High grade and advanced stage IGCs have significantly higher survivin positivity and expression than low grade and early stage IGCs. Males have higher positivity and expression for p27 and survivin than females. Conclusion: Inverse relation between p27 and survivin in H. pylori gastritis, H. pylori gastritis with IM and IGCs lesions, suggesting that both proteins could be used as potential prognostic and/or diagnostic biomarkers in H. pylori and IM associated- gastritis as well as in IGC.     

Influence of Gastric pH Modifiers on Development of Intestinal Metaplasia Induced by X-Irradiation in Rats

The influence of gastric pH on intestinal metaplasia was examined in male Crj:CD(SD) rats. At the age of 5 weeks, animals were irradiated with two 10 Gy doses of X-rays to the gastric region at a 3-day interval (total 20 Gy), and 6 months after irradiation, received either secretin or histamine in silicon tubes for 2 months or had their bilateral submandibular salivary glands removed. The incidences of intestinal metaplasia in the fundus of animals after administration of secretin or histamine, or removal of the salivary glands were reduced, along with the pH values, as compared with values for rats given X-rays alone. In both the pyloric and the fundic gland mucosae, the numbers of alkaline phosphatase (ALP)-positive foci and type B metaplasias (intestinal crypts without Paneth cells) were also significantly decreased (P<0.01). In a second experiment, started six months after irradiation, rats were kept on 1% sodium chloride (NaCl) diet for 6 months. Subsequent removal of salivary glands along with histamine treatment brought about a marked drop in pH and in numbers of ALP-positive foci after three and five days. The present results thus indicated that development and maintenance of intestinal metaplasia can be influenced by a decrease of pH value.     

Effects of the Hippo Signaling Pathway in Human Gastric Cancer

Background/Aim: The Hippo signaling pathway is a newly discovered and conserved signaling cascade,which regulates organ size control by governing cell proliferation and apoptosis. This study aimed to investigateits effects in human gastric cancer. Methods: Tumor tissues (n=60), adjacent non-tumor tissues (n=60) andnormal tissues (n=60) were obtained from the same patients with primary gastric cancer (GC). In addition,70 samples of chronic atrophic gastritis (CAG) tissues were obtained from patients with intestinal metaplasia(IM) by endoscopic biopsy. Hippo signaling molecules, including Mst1, Lats1, YAP1, TAZ, TEAD1, Oct4 andCDX2, were determined by quantitative polymerase chain reaction (qPCR). Protein expression of Mst1, Lats1,YAP1, TEAD1 and CDX2 was assessed by immunohistochemistry and Western blotting. Results: Mst1, Lats1and Oct4 mRNA expression showed an increasing tendency from GC tissues to normal gastric tissues, while themRNA expression of YAP1, TAZ and TEAD1 was up-regulated (all P<0.01). Mst1 and Lats1 protein expressionpresented a similar trend with their mRNA expression. In addition, YAP1 and TEAD1 protein expression in GCwas significantly higher than in the other groups (all P<0.01). CDX2 mRNA and protein expression in the CAGgroup were higher than in the other groups (all P<0.01). In GC, mRNA expression of Mst1, Lats1, Oct4, YAP1,TAZ, TEAD1 and CDX2 had a close correlation with lymphatic metastasis and tumor TNM stage (all P<0.01).Furthermore, protein expression of Mst1, Lats1 ,YAP1, TAZ, TEAD1 and CDX2 had a close correlation betweeneach other (P<0.05). Conclusion: The Hippo signaling pathway is involved in the development, progression andmetastasis of human gastric cancer. Therefore, manipulation of Hippo signaling molecules may be a potentialtherapeutic strategy for gastric cancer.     

Risk of gastric cancer among patients with gastric intestinal metaplasia

Plenty of studies have assessed the association between intestinal metaplasia (IM) and gastric cancer risk, while the results were inconsistent. We aimed to assess the risk of gastric cancer among patients with IM. Systematic literature searches were conducted in PubMed, Embase and Cochrane databases. Baseline characteristics and outcomes from the included studies were extracted independently by two investigators. Either a fixed‐effects or a random‐effects model was used to composite the pooled OR for gastric cancer risk. Finally, a total of 21 studies, which comprised 402,636 participants and 4,535 gastric cancer patients, were finally included in the current meta‐analysis. Compared with those participants without IM, IM patients were at a higher risk of gastric cancer (pooled OR = 3.58, 95% CI 2.71–4.73). We observed that incomplete IM (pooled OR = 9.48, 95% CI 4.33–20.78) but not complete IM (pooled OR = 1.55, 95% CI 0.91–2.65) was significantly associated with a higher gastric cancer risk. Besides, it appeared that gastric cancer risk was higher among patients with IM in the corpus (pooled OR = 7.39, 95% CI 4.94–11.06) than those with IM in the antrum only (pooled OR = 4.06, 95% CI 2.79–5.91). And the pooled ORs for gastric noncardia cancer and gastric cardia cancer were 4.98 (95% CI 3.12–7.95) and 1.93 (95% CI 1.15–3.24), respectively. In conclusion, patients with IM were at a higher risk of gastric cancer, especially for incomplete IM and IM in the corpus. The current evidence supports the use of IM subtypes in the surveillance of gastric cancer.     

胃癌分子分型研究进展

胃癌是全球性常见的恶性肿瘤.胃癌是一种异质性疾病包括多种类型,每种类型都有不同的生物学特性和作用.因此,基于临床特点,病理分型,分子分型的个体化治疗对进展期胃癌尤为重要.现有的胃癌分子分型可归类为Shah分型,Tan基因分型,新加坡基因分型,TCGA基因分型和ACRG基因分型.从分子生物学创立引起肿瘤治疗模式的变化,从分子水平重新认识疾病,未来的肿瘤治疗模式可能是分子分型指导的个体化治疗.     

Promoter hypermethylation of tumor-related genes in gastric intestinal metaplasia of patients with and without gastric cancer

Promoter hypermethylation is an alternative mechanism of gene silencing in human cancers including gastric cancer. While intestinal metaplasia (IM) is generally regarded as a precancerous lesion of the stomach, our study examines the presence of gene promoter hypermethylation in IM of patients with and without gastric cancer. We examined 31 samples of gastric cancer, 36 gastric IM (21 associated with gastric cancer and 15 from noncancer patients) and 10 normal gastric biopsies. Tissues containing foci of IM were carefully microdissected from paraffin-embedded section. Bisulfite-modified DNA was examined for gene promoter hypermethylation in DAP-kinase, E-cadherin, GSTP1, p14, p15, p16, RASSF1A and hMLH1 by methylation-specific-PCR. None of the control gastric tissues had hypermethylation detected, but gene promoter hypermethylation was frequently detected in gastric cancer and IM. The mean number of methylated genes in cancer and IM was 3.0 and 1.4, respectively (p < 0.0001). Methylation in IM from cancer patients was all associated with concurrent methylation in the corresponding tumor samples. The numbers of methylated genes were similar in IM obtained from cancer and noncancer patients. By examining the methylation patterns of these genes, 3 differential methylation patterns were recognized: hypermethylation was more frequent in cancer than in IM (DAP-kinase, p14, p15 and p16); comparable frequencies of methylation in cancer and IM (E-cadherin and hMLH1); and no methylation (GSTP1). Aberrant methylation in tumor-related genes is frequently detected in gastric IM of both cancer and noncancer patients, suggesting their early involvement in the multistep progression of gastric carcinogenesis.     

Genomic and Transcriptomic Profiling of Combined Hepatocellular and Intrahepatic Cholangiocarcinoma Reveals Distinct Molecular Subtypes

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Villin蛋白的表达及其与贲门腺癌的关系

目的 探讨Villin蛋白在贲门肠化中的作用及其与贲门腺癌(GCA)发生、发展的关系.方法 采用免疫组织化学S-P法检测128例胃镜活检及手术切除的GCA及癌旁肠化组织中Villin蛋白的表达,其中贲门肠化组织25例、肠化伴不典型增生组织48例,GCA组织55例,并选取15例胃镜普查正常贲门组织作为对照.结果 Villin蛋白在正常贲门组织中无阳性表达,在贲门肠化组织中的阳性表达率为76.0%(19/25),肠化伴不典型增生组织中的阳性表达率为60.4%(29/48),GCA组织中的阳性表达率为36.4%(20/55),比较差异有统计学意义(P<0.05).Villin蛋白的表达与GCA的分化程度有关(P<0.05).结论 Villin蛋白参与了贲门组织早期肠化和GCA的发生,并在GCA的细胞分化中起重要作用.