Relation of overexpression of S phase kinase-associated protein 2 with reduced expression of p27 and PTEN in human gastric carcinoma

AIM: To investigate the significance of S phase kinase associated protein 2 (Skp2) expression in human gastric carcinoma and the relation between expressions of Skp2, p27 and PTEN. METHODS: Immunohistochemical analysis was performed on 138 gastric carcinoma specimens, their paired adjacent mucosa specimens, 102 paired lymphatic metastatic carcinoma tissue specimens, 30 dysplasia specimens, 30 intestinal metaplasia specimens, 10 chronic superficial gastritis specimens and 5 normal gastric mucosa specimens for Skp2 expression and on 138 gastric carcinoma specimens for p27 and PTEN expression. RESULTS: Skp2 labeling frequency was significantly higher in intestinal metaplasia (12.68±0.86) and adjacent mucosa (19.32±1.22) than in normal gastric mucosa (0.53±0.13) and chronic superficial gastritis (0.47±0.19) (P = 0.000); in dysplasia (16.74±0.82) than in intestinal metaplasia (P = 0.000); in gastric primary carcinoma (31.34±2.17) than in dysplasia and adjacent mucosa (P = 0.000); in metastasis gastric carcinoma in lymph nodes (39.76±2.00) than in primary gastric carcinoma (P = 0.037), respectively. Skp2 labeling frequency was positively associated with differentiation degree (rho = 0.315, P = 0.000), vessel invasion (rho = 0.303, P = 0.000) and lymph node metastasis (rho = 0.254, P = 0.000) of gastric cancer. Expression of Skp2 was negatively associated with p27 (rho = -0.451, P = 0.000) and PTEN (rho = -0.480, P = 0.000) expression in gastric carcinoma. p27 expression was positively associated with PTEN expression in gastric carcinoma (rho = 0.642, P = 0.000). CONCLUSION: Skp2 overexpression may be involved in carcinogenesis and progression of human gastric carcinoma in vivo, possibly via p27 proteolysis. PTEN may regulate the expression of p27 by negatively regulating Skp2 expression.     

E-cad基因表达与胃癌发生及预后的关系研究

为探讨上皮钙粘附蛋白（E-cad)基因表达与胃癌发生发展及预后的关系，应用免疫组织化学方法检测了65例胃癌，25例胃癌前病变患者及20例胃粘膜正常者标本中的E-cad表达。结果显示，胃癌E-cad异常表达率（53．85％）显著高于胃癌前病变（24．0％），E-cad表达异常与胃癌的临床分期，分化程度，浸润深度及淋巴结转移密切相关，E-cad表达正常胃癌患者的3年，5年生存率显著高于E-cad表达异常者（P＜0．05）。提示E-cad基因表达与胃癌发生发展密切相关，检测E-cad表达有助于胃癌的早期诊断及转移潜能与预后的判断。     

PTEN encoding product： a marker for tumorigenesis and progression of gastric carcinoma

AIM: To detect the expression of PTEN encoding productin normal mucosa, intestinal metaplasia (IM), dysplasia andcarcinoma of the stomach, and to investigate its clinicalimplication in tumorigenesis and progression of gastriccarcinoma.METHODS: Formalin-fixed paraffin embedded specimens from184 cases of gastric carcinoma, their adjacent normal mucosa,IM and dysplasia were evaluated for PTEN protein expressionby SABC immunohistochemistry. PTEN expression wascompared with tumor stage, lymph node metastasis, Lauren'sand WHO's histological classification of gastric carcinoma.Expression of VEGF was also detected in 60 cases of gastriccarcinoma and its correlation with PTEN was concerned.RESULTS: The positive rates of PTEN protein were 100 %(102/102), 98.5 %(65/66), 66.7 % (4/6) and 47.8 %(88/184)in normal mucosa, IM, dysplasia and carcinoma of the stomach,respectively. The positive rates in dysplasia and carcinomawere lower than in normal mucosa and IM (P＜0.01).Advanced gastric cancers expressed less frequent PTEN thanearly gastric cancer (42.9 % v567.6 %, P＜0.01). The positiverate of PTEN protein was lower in gastric cancer with thanwithout lymph node metastasis (40.3 % v563.3 %, P＜0.01).PTEN was less expressed in diffuse-type than in intestinal-type gastric cancer (41.5 % v557.8 %,P＜0.05). Signet ringcell carcinoma showed the expression of PTEN at the lowestlevel (25.0 %, 7/28); less than well and moderatelydifferentiated ones (P＜0.01). Expression of PTEN was notcorrelated with expression of VEGF (P＞0.05).CONCLUSION: Loss or reduced expression of PTEN proteinoccures commonly in tumorigenesis and progression of gastriccarcinoma. It is suggested that PTEN can be an objective markerfor pathologically biological behaviors of gastric carcinoma.     

Malignant degeneration of Barrett''s esophagus: the role of the Ki-67 proliferation fraction, expression of E-cadherin and p53

Barrett's columnar epithelium with dysplasia is the most important risk factor for adenocarcinoma of the distal esophagus. The molecular mechanisms responsible for progression of columnar metaplasia to dysplasia and invasive carcinoma are mostly unknown. We investigated expression of the tumor suppressor gene p53, E-cadherin expression and cell proliferation in the metaplasia-dysplasia-carcinoma sequence of esophageal adenocarcinoma. In 24 patients with R0-resected adenocarcinomas of the distal esophagus we evaluated the expression of E-cadherin (antibody HECD-1), mutated p53 (antibody DO1) and cell proliferation (antibody MiB1) by immunohistochemistry in sections of adenocarcinoma, columnar metaplasia, with and without dysplasia, and in squamous epithelium of the esophagus. No p53 immunoreactivity was seen in sections of normal squamous epithelium or columnar metaplasia. Fifty per cent of invasive adenocarcinomas stained positive for mutated p53. The p53 expression correlated with the T-category (P = 0.048) and the N-category (P = 0.024). There was a significant decrease in the expression of E-cadherin from columnar metaplasia to dysplasia and to esophageal adenocarcinoma (P < 0.0001). Expression of E-cadherin in columnar metaplasia without dysplasia was similar to that seen in normal squamous epithelium of the esophagus. The Ki-67 proliferation fraction increased significantly from normal squamous epithelium to columnar metaplasia to dysplasia and to invasive carcinoma (P < 0.001), with a marked expansion of the proliferative component. There was no correlation between cell proliferation, E-cadherin expression and the tumor stage. In contrast to the alterations in the p53 expression, a decreased E-cadherin expression and the expansion of the proliferative component represent an early phenomenon in the malignant degeneration of Barrett's esophagus. This might aid in the early detection of esophageal adenocarcinoma.     

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.     

CD44v6: a potential marker of malignant transformation in intestinal metaplasia of the stomach? An immunohistochemical study using tissue microarrays

OBJECTIVE: Intestinal metaplasia is a well-established risk factor in the development of stomach cancer. However, since the specificity is low it would be of great practical value to find a marker to separate cases of intestinal metaplasia into low and high risk for progression to dysplasia/carcinoma. So far this has not been achieved. CD44 is a cell surface molecule involved in cell-cell and cell-matrix interactions, and the spliced variant 6 has been shown to play a role in the progression of gastric carcinoma. The aim of this study was therefore to evaluate CD44v6 as a marker of increased cancer risk in intestinal metaplasia. METHODS: The current study investigated immunohistochemical CD44v6 expression in biopsies of normal gastric mucosa (n = 154) and gastric mucosa with intestinal metaplasia (n = 127). A third group consisted of cancer gastrectomies (n = 117) in which both tumour and uninvolved mucosa was studied. Proximal (cardia) and distal (corpus/antrum) locations were noted in all cases. RESULTS: There was a significant sequential increase in CD44v6 expression from normal mucosa and mucosa showing intestinal metaplasia to uninvolved mucosa adjacent to cancers without and with intestinal metaplasia to tumour. The most striking increase was from 'normal' to intestinal metaplastic mucosa adjacent to cancers. There were no differences between proximal and distal cases in any group. CONCLUSION: These findings strongly suggest that CD44v6 expression is a late phenomenon in the transformation of intestinal metaplasia to dysplasia/cancer. It may therefore be a useful marker of cancer risk in patients with intestinal metaplasia.     

Hp感染与老年胃癌及癌前病变中bcl-2、p16、c-myc基因表达的关系

目的　研究幽门螺杆菌 (Hp)感染的老年胃癌及癌前病变 bcl- 2、 p1 6、 c- myc基因蛋白的表达。方法　 bcl- 2、 p1 6、 c- myc蛋白检测采用免疫组化方法 ,快速尿素酶法和 HE染色确定 Hp感染。结果　 c- myc在胃癌中阳性表达率显著高于异型增生 (P<0 .0 5)。 bcl- 2在异型增生组织中的阳性表达率与胃癌、肠上皮化生相比无显著性差异 (P>0 .0 5)。bcl- 2与胃癌类型、分化程度显著相关 (P<0 .0 5)。Hp阳性组 bcl- 2、c-myc阳性表达率均高于 Hp阴性组 ,两者之间有显著性差异 (P<0 .0 5)。 p1 6在慢性胃炎中阳性表达率显著高于胃癌 (P<0 .0 5)。 Hp阳性萎缩性胃炎 p1 6阳性表达率低于 Hp阴性组 (P<0 .0 5)。结论　 Hp感染可以引起抑癌基因 p1 6表达低下 ,c- myc、bcl- 2基因蛋白表达增加 ,Hp可能为促癌剂在胃癌的发生发展中起一定作用。     

Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer

BACKGROUND:E-cadherin is an adhesion molecule involved in tumour invasion/metastasis. Silencing of E-cadherin by promoter CpG methylation has been shown in both familial and sporadic gastric cancers. Helicobacter pylori is a class I carcinogen in gastric cancer. AIMS: This study was undertaken to investigate the association between methylation of E-cadherin and H pylori in gastric mucosa from dyspeptic patients, and in intestinal metaplasia and primary and metastatic adenocarcinoma from surgical specimens of patients with gastric cancer. METHODS: E-cadherin methylation was studied using methylation specific polymerase chain reaction in microdissected tissue from biopsies or surgical resection specimens. E-cadherin expression was studied by immunohistochemistry. RESULTS: E-cadherin methylation was present in 31% (11/35) of gastric mucosae from dyspeptic patients, and was associated with H pylori infection (p=0.002), but was independent of the age of the patient or presence or absence of gastritis. E-cadherin methylation was present in 0% (0/8) of normal mucosa, 57% (12/21) of intestinal metaplasias, and 58% (15/26) of primary and 65% (21/32) of metastatic cancers. E-cadherin methylation status was concordant in 92% (11/12) of intestinal metaplasias and primary cancers, and in 85% (17/20) of primary and metastatic cancers from the same resected specimen. E-cadherin methylation in gastric cancer was associated with depth of tumour invasion (p=0.02) and regional nodal metastasis (p=0.05). CONCLUSION:E-cadherin methylation is an early event in gastric carcinogenesis, and is initiated by H pylori infection.     

胃癌发生过程中凋亡基因Survivin与Fas表达及其与幽门螺杆菌感染的关系

目的探讨凋亡基因Survivin、Fas在胃癌发生过程中的表达、临床意义及和幽门螺杆菌（Hp）感染的关系。方法采用分子原位杂交分别检测12例正常胃黏膜、22例浅表性胃炎、25例肠上皮化生、37例异型增生及52例胃癌组织中的Survivin-mRNA和Fas-mRNA表达，并检测患者Hp感染状况。结果Survivin-mRNA在肠上皮化生、异型增生组和胃癌组织中的阳性率分别为28．0％、43．2％和69．2％。胃癌组明显高于肠化和异型增生组（P〈0．01；P〈0．05）。胃癌组Fas-mRNA阳性率为36．5％，显著低于对照组和异型增生组（P均〈0．01）。Survivin-mRNA在高分化、中分化和低分化及未分化型胃癌组织中阳性率呈现递增趋势，而且其表达和淋巴结转移、远处转移密切相关。Fas-mRNA阳性率在高、中和低分化及未分化型胃癌患者中呈现递减趋势，且其表达和淋巴结转移密切相关。异型增生患者Survivin-mRNA表达与Hp感染之间呈明显正相关（P〈0．01）。相关回归分析显示胃癌患者各病理分期中Survivin-mRNA与Fas-mRNA表达呈负相关。结论在胃黏膜癌变过程中，Survivin的表达和作用逐渐上调，而Fas的表达和作用逐渐下调，而且在癌前病变组织中Survivin表达和Hp感染有密切关系；在胃癌组织中Survivin和Fas的表达呈负相关。     

慢性萎缩性胃炎黏膜上皮中P53和C-erbB-2表达的临床意义

目的:探讨慢性萎缩性胃炎(CAG)黏膜上皮中P53及C-erbB-2的表达及意义．方法:用免疫组化技术(SP法)检测正常胃黏膜56例、慢性萎缩性胃炎429例(腺体囊性扩张61例,大肠型化生73例,轻、中、重度不典型增生各120、91和84例)和早期胃癌57例中P53和C-erbB-2的表达,分析P53和C-erbB-2表达及其与CAG胃黏膜病变类型的关系．结果:正常胃黏膜,囊性扩张腺体,轻、中度不典型增生,大肠型化生,重度不典型增生,早期胃癌P53和C-erbB-2表达的阳性率呈上升趋势．前三组间表达率差异无统计学意义(P>0．05);正常胃黏膜与中度不典型增生、大肠型化生、重度不典型增生及胃癌组P53和C-erbB-2的表达差异有统计学意义(P<0．01)．Spearman等级相关分析显示P53和C-efbB-2表达呈正相关(r=0．867,P<0．05)．年龄<40岁和≥40岁组间、性别组间P53表达阳性率差异有统计学意义(x2=12．393,P<0．01;x2=8．799, P<0．01)．C-erbB-2的表达在上述年龄组间差异有统计学意义(x2=7．706,P<0．01),而在性别组间无统计学意义(P>0．05)．结论:检测慢性萎缩性胃炎中P53和C-erbB-2的表达,有助于监测CAG癌前病变的进展及胃癌的早期发现．     

胃癌、癌旁组织中抑癌基因和凋亡调节基因表达及其内在关系

目的 研究胃癌、癌旁组织中抑癌基因ｐ５３、ｐ１６和关键性凋亡调节基因ｂｃｌ－２蛋白的表达及其内在的关系,进一步探讨胃癌发病可能的分子机制。方法 术中取３０例胃癌患者的癌组织,癌旁组织各２块,石蜡包埋,切片分别作ＨＥ染色病理检查及免疫组织化学检查ｐ５３、ｐ１６、ｂｃｌ－２基因蛋白表达。结果 ｐ５３、ｐ１６和ｂｃｌ－２表达与胃癌分期、分化程度及有无淋巴结转移均无显著关系（Ｐ〉０．０５）,但ｂｃｌ－２与     

胃癌及癌前病变中p53蛋白的检测及意义

探讨p53蛋白表达与胃癌及癌病变的相互关系,方法：用免疫组化染色示检测33例肠化,26例异型增生和26例胃癌组织中p53蛋白的表达。结果：p53蛋白在胃癌组织中表达率最高（61．5％）,在异型增生和肠化组织中的表达率分别为34．6％和12．1％,组间有显著差异,各期胃癌组织中p53蛋白的表达无显著差异,结论：p53蛋白在胃癌前病变中已有阳性表达,在肠化、异型增生及胃癌组织中,其表达率依次增高,p53蛋白积累主要发生在癌前病变晚期及胃癌早期,其表达与胃癌发生密切相关。     

Expression of E—cadherin and β—catanin in gastric carcinoma and its correlation with the clinicopathological features and patient survival

AIM:The E-cadherin-catedin complex is important for cell-cell adhesion of epithelial cells.Impairment of one or more components of this comples is associated with poor differentiation and increased invasiveness of carcinomas,We evaluated the expression pattern of E-cadherin and β-catenin in gastric carcinoma and dysplasia and analyzed their relationship with tumor clinicopathological featrres and patient survival.     

Effect of Helicobacter pylori infection on gastric epithelial proliferation in progression from normal mucosa to gastriccarcinoma

ＥｆｅｃｔｏｆＨｅｌｉｃｏｂａｃｔｅｒｐｙｌｏｒｉｉｎｆｅｃｔｉｏｎｏｎｇａｓｔｒｉｃｅｐｉｔｈｅｌｉａｌｐｒｏｌｉｆｅｒａｔｉｏｎｉｎｐｒｏｇｒｅｓｓｉｏｎｆｒｏｍｎｏｒｍａｌｍｕｃｏｓａｔｏｇａｓｔｒｉｃｃａｒｃｉｎｏｍａＬＩＵＷｅｎＺｈｏｎ...     

胃癌和胃癌前病变中环氧合酶-2、p16的表达及其临床意义

背景：密切监测胃癌前病变是预防和及早发现胃癌的关键。目的：观察胃癌及其癌前病变中环氧合酶-2（COX-2）、p16的表达,探讨两者对胃癌早期诊断的意义。方法：以免疫组化染色检测20例正常胃黏膜、60例肠化生、60例上皮内瘤变和60例胃癌组织中COX-2和p16的表达,并分析两者的相关性。结果：正常胃黏膜、肠化生、上皮内瘤变和胃癌组织中的COX-2表达呈递增趋势,p16表达呈递减趋势。高级别上皮内瘤变和早期、进展期胃癌组织COX-2、p16表达阳性率与正常胃黏膜和肠化生组织相比差异有统计学意义（P〈0.05）,而前三者之间以及后两者之间无明显差异。COX-2、p16表达阳性率在小肠化生、完全型大肠化生与不完全型大肠化生之间以及早期与进展期胃癌之间无明显差异,但在高级别与低级别上皮内瘤变中差异有统计学意义（P〈0.05）。COX-2表达与p16表达呈负相关（P〈0.001）。早期胃癌组织中COX-2表达阳性同时p16表达阴性的比例显著高于高级别上皮内瘤变组织（P〈0.05）。结论：COX-2、p16或两者联合检测有助于监测和随访胃癌前病变、筛选胃癌高危人群,为胃癌的早期诊断提供了重要的检测方法。