肿瘤抑制基因PTEN在胃癌中的表达及其临床意义

目的　研究第 10号染色体同源丢失性磷酸酶 -张力蛋白基因 (phosphatase and tensin homology delet-ed on chrom osom e ten,PTEN)在胃癌组织中的表达水平以及与生物学行为的关系和对预后评价的意义。方法　以免疫组化方法检测 10 6例胃癌组织中 PTEN蛋白的表达水平。结果　 10 6例胃癌中 ,PTEN表达阳性 72例(6 7.9% ) ,其中弱阳性 15例 (14 .1% ) ,强阳性 5 7例 (5 3.8% )。在胃癌组织中 ,PTEN蛋白水平与胃壁浸润深度、组织分化类型 ,临床分期等相关 (P<0 .0 5 ) ;单变量生存分析 ,PTEN蛋白阳性表达组 3、5年生存率分别为 4 8.6 %、37.5 % ,高于阴性表达组 32 .4 % ,11.8% ,但经 L og- rank时序检验示差异无显著性 (P=0 .0 72 1)。 Cox回归模型多变量分析显示 ,PTEN不是一个独立的预后指标。结论　 PTEN与胃癌的发生发展有关 ,但不是判断胃癌预后的一个独立指标     

PTEN 表达与胃癌预后因素分析

目的：探讨胃癌组织中PTEN（张力蛋白和辅助蛋白同源、第10号染色体丢失的磷酸酶基因）和MMP-2（基质金属蛋白酶-2）蛋白表达与患者预后的关系。方法：用免疫组织化学S—P法检测64例胃癌组织PTEN和MMP-2蛋白表达，并对随访的33例胃癌患者进行单因素及多因素生存分析，选用Cox比例风险模型进行多因素生存分析。结果：PTEN蛋白在胃癌组织表达缺失率为21．98％，其表达缺失与淋巴结转移正相关，与患者生存期负相关（P〈0．05），Cox回归多因素生存分析显示PTEN蛋白表达缺失的患者生存的相对危险度是PTEN表达阳性的0．273倍（P〈0．05）；MMP-2蛋白在胃癌组织表达阳性率为68．75％，其高表达与癌细胞浸润深度、淋巴结转移呈正相关，与生存期呈负相关（P〈0．05）。另外，根治手术与患者的生存期呈正相关（P〈0．05），非根治术患者生存的相对危险度是根治术患者的1．104倍（P〈0．05）。结论：PTEN蛋白可作为胃癌患者预后的独立预测因子，PTEN蛋白表达缺失的胃癌患者预后不良。     

胃癌中PTEN突变在其蛋白异常表达中的作用

背景与目的：胃癌组织中PTEN蛋白表达缺失率较高，本文旨在探讨胃癌组织中PTEN基因突变在其蛋白异常表达中的作用。方法：应用PCR—SSCP—DNA测序和免疫组织化学技术检测53例胃癌组织中PTEN基因突变及其蛋白表达水平的改变。结果：53例胃癌组织中共检测到5例PTEN基因突变，突变率仅为9．4％，低于PTEN蛋白表达缺失率（34．0％）。此5例突变阳性胃癌组织中的PTEN蛋白表达情况为4例阴性、1例弱阳性。结论：基因突变是胃癌组织中PTEN蛋白异常表达的原因之一，突变以外的其他异常改变可能在这一过程中发挥了更为重要的作用。     

PTEN和hMLH1蛋白的表达与胃癌发生及生物学行为的关系

目的探讨PTEN和hMLH1蛋白表达与胃癌发生及生物学行为的关系。方法免疫组化SP法检测80例胃腺癌细胞和68例非癌胃黏膜上皮细胞PTEN和hMLH1蛋白的表达情况,分析二者表达与胃癌生物学行为的关系。结果胃癌组PTEN蛋白的阳性表达率77.5%低于非癌胃黏膜组的91.2%(P<0.05),胃癌低分化组PTEN蛋白的阳性表达率61.1%低于高中分化组的88.6%(P<0.01);胃癌组hMLH1蛋白的阳性表达率67.5%高于非癌胃黏膜组的32.4%(P<0.01),低分化组hMLH1蛋白的阳性表达率50.0%低于高中分化组的81.8%(P<0.01),有淋巴结转移组hMLH1蛋白的阳性表达率85.7%高于无淋巴结转移组的57.7%(P<0.05)。胃癌细胞PTEN和hMLH1蛋白表达呈正相关(P<0.01)。结论PTEN蛋白表达下调可能与胃癌发生有关,而hMLH1在胃癌组的表达可能与代偿性修复有关。PTEN和hMLH1蛋白表达也会影响胃癌的部分生物学行为,其机制可能是hMLH1基因功能缺陷导致PTEN基因表达下调。     

PTEN基因编码产物与胃癌发生发展相关性的研究

目的 :观察抑癌基因PTEN编码蛋白在正常胃黏膜、肠上皮化生及胃癌组织中的表达 ,探讨PTEN与胃癌发生发展的关系及作用机制。方法 :采用sABC免疫组化方法检测 184例胃癌及其癌旁肠上皮化生组织中PTEN蛋白表达 ,比较其与胃癌的WHO组织学分型、Lauren分型、临床病理分期及淋巴结转移的关系 ;另对其中 6 8例胃癌同时检测血管内皮生长因子 (VEGF)并比较它与PTEN蛋白表达的关系。结果 :胃癌组织PTEN蛋白表达显著低于正常胃黏膜 (47 8%vs 10 0 % ,P <0 0 1)。弥漫型胃癌PTEN表达显著低于肠型胃癌 (41 5 %vs 5 7 8% ,P <0 0 5 ) ;弥漫型胃癌癌旁肠上皮化生组织PTEN蛋白表达显著低于肠型胃癌旁肠化组织 (5 2 5 %vs 10 0 % ,P <0 0 1) ;进展期胃癌PTEN表达显著低于早期胃癌 (40 9%vs 6 7 6 % ,P <0 0 1) ;PTEN蛋白表达降低或失活与胃癌淋巴结转移显著正相关 (转移组4 0 3%vs非转移组 6 3 3% ,P <0 0 1) ;PTEN蛋白与VEGF表达 (31/6 8,4 5 6 %vs 5 1/6 8,75 0 % )呈一定负相关。结论 :PTEN失活或蛋白表达降低与胃癌细胞分化程度、临床病理分期及转移能力密切相关。提示PTEN基因编码产物的检测可作为判定胃癌发生及侵袭转移能力的一项客观指标     

胃癌中CD44v6和PTEN表达及意义

[目的]探讨CD44v6和PTEN蛋白在胃癌中的表达及意义。[方法]采用免疫组织化学方法检测73例胃癌组织和25例正常胃黏膜组织中CD44v6和PTEN蛋白表达,并分析其与临床病理特征间的意义。[结果]73例胃癌组织中CD44v6阳性表达率为71.2%,显著高于正常胃黏膜组织的20.0%（χ2=20.09,P〈0.01）;PTEN蛋白表达阳性率为30.1%,显著低于正常胃黏膜组织的100.0%（χ2=36.42,P〈0.01）;CD44v6高表达和PTEN蛋白低表达与胃癌的分化程度、浸润深度及淋巴结转移密切相关（P〈0.05）,胃癌组织中CD44v6与PTEN蛋白表达呈负相关（χ2=14.06,P〈0.01）。[结论]胃癌组织中CD44v6的高表达与PTEN蛋白的低表达与胃癌的发生、发展、浸润转移密切相关,联合检测CD44v6和PTEN蛋白表达可评估胃癌侵袭转移能力,对胃癌的预后判断具有一定的临床意义。     

PTEN编码产物在胃癌发生发展不同阶段中的表达及意义

目的观察抑癌基因PTEN编码蛋白在癌旁胃黏膜、肠上皮化生、异型增生及胃癌组织中的表达,探讨PTEN表达在胃癌发生发展过程中的作用.方法采用SABC免疫组化方法检测了184例胃癌及癌旁胃黏膜、肠上皮化生和异型增生中的PTEN蛋白表达,比较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.并检测了其中60例胃癌中血管内皮生长因子(VEGF)的蛋白表达,比较VEGF与PTEN蛋白表达的关系.结果 PTEN蛋白在癌旁胃黏膜、肠化生、异型增生和胃癌中的阳性表达率分别为100.0%(102/102)、98.5%(65/66)、66.7%(4/6)和47.8%(88/184),后两者的阳性率均显著低于前两者(P<0.01);进展期胃癌PTEN表达显著低于早期胃癌( 42.9%∶67.6%,P<0.01);PTEN蛋白表达降低与胃癌淋巴结转移呈显著正相关(40.3%∶ 63.3%, P< 0.01);弥漫型胃癌PTEN表达显著低于肠型胃癌(41.5%∶57.8%,P<0.05);印戒细胞癌中PTEN表达最低(25.0%,7/28),显著低于高中分化管状腺癌(P< 0.01).PTEN蛋白与VEGF蛋白表达呈负相关趋势,但差异无显著性(P>0.05).结论 PTEN基因编码蛋白在胃癌发生发展不同阶段表达呈进行性下调或缺失,可能系通过降低细胞黏附、促进血管形成和提高细胞运动性等途径参与胃癌的发生和演进过程.PTEN蛋白表达水平可作为判定胃癌病理生物学行为的客观指标.     

抑癌基因PTEN、一氧化氮合酶与胃癌的关系及临床意义

目的检测抑癌基因PTEN编码蛋白、iNOS在正常胃粘膜及胃癌组织中的表达情况,探讨PTEN、iNOS与胃癌发生发展的关系及作用机理.方法采用免疫组织化学S-P法进行检测.结果 10例正常胃粘膜均可见PTEN蛋白的强表达,40例胃癌组织中28例PTEN蛋白表达较正常胃粘膜明显下降或缺失,差异有显著性(P＜0.01),与胃癌的分化程度、浸润深度、TNM分期、淋巴结转移显著相关(P＜0.05).iNOS在胃癌组织中的表达显著高于正常胃粘膜组,(72.5%vs10%,P＜0.01),与胃癌的浸润深度、淋巴结转移、TNM分期显著相关(P＜0.05).在PTEN蛋白阴性的胃癌组中,iNOS阳性率为93.8%,显著高于PTEN阳性组(P＜0.05).结论抑癌基因PTEN编码蛋白在胃癌及胃癌发展过程中表达逐渐下降或缺失,与iNOS之间可能存在相互作用,协同参与了胃癌的发展、转移及浸润.PTEN蛋白表达可作为判定胃癌生物学行为的临床参考指标.     

胃癌中PTEN和p-AKT蛋白的表达及其临床意义与预后分析

目的:探讨PTEN (phosphatase and tensin homologue deleted on chromosome ten)和磷酸化AKT(phosphorylated-AKT,p-AKT)蛋白在胃癌中的表达及其临床意义,评价其在胃癌预后方面的作用.方法:收集229例随访超过5年的胃癌患者肿瘤组织标本,制作成组织芯片,应用免疫组织化学的方法检测PTEN和p-AKT蛋白的表达,并将检测结果与患者的临床病理特征和生存期进行统计分析.结果:胃癌组织中PTEN和p-AKT蛋白的阳性表达率分别为45.9％和55.9％,均高于相应癌旁组织(P＜0.05).PTEN和p-AKT蛋白表达与肿瘤TNM分期、浸润深度和脉管浸润有关(P＜ 0.05); PTEN蛋白在肠型胃癌组织中的阳性表达率较弥漫型胃癌组织中高,差异有统计学意义(P＜0.05);p -AKT蛋白表达与Lauren分型无关,但与淋巴结转移有关(P＜0.01).PTEN蛋白阳性表达和阴性表达患者的生存率无明显差异(P＞0.05),p-AKT蛋白阳性表达患者的生存率低于阴性表达者,差异有统计学意义(P＜0.05).结论:PTEN和p-AKT蛋白表达与胃癌的发生、发展、侵袭和转移有关.p-AKT蛋白表达是胃癌的预后因素.     

PTEN基因甲基化与胃癌临床病理特征的关系

目的研究胃癌组织中抑癌基因第10号染色体缺失性磷酸酶张力蛋白基因（PTEN）表达异常与胃癌临床病理特征的关系。方法应用甲基化特异性PCR方法（MSP）检测45例胃癌及癌旁正常组织PTEN甲基化的表达情况。结果40．0％（18／45）的胃癌组织和2．2％（1／45）的癌旁正常组织PTEN基因发生甲基化,胃癌组织甲基化率显著增高（P〈0．05）;低分化腺癌甲基化率为60．0％（15／25）,高中分化腺癌甲基化率为15．0％（3／20）,二者差异具有统计学意义（P〈0．05）;发生淋巴结转移的24例胃癌组织中,13例PTEN基因发生甲基化,发生淋巴结转移的胃癌组织PTEN甲基化率明显高于无淋巴结转移胃癌组织（P〈0．05）。结论PTEN基因甲基化与胃癌的发生密切相关,PTEN基因甲基化在胃癌的发病过程中起重要作用。     

PTEN induces G(1) cell cycle arrest and decreases cyclin D3 levels in endometrial carcinoma cells

Inactivating mutations in the PTEN tumor suppressor gene occur in approximately 30-50% of endometrial carcinomas. PTEN is a phosphatase that negatively regulates the phosphoinositide 3-kinase signaling pathway, including the downstream effector AKT. To evaluate the role of PTEN in endometrial growth regulation, we expressed wild-type or mutant PTEN in endometrial carcinoma cell lines. As expected, expression of exogenous PTEN decreased levels of activated AKT in all cell lines examined. However, PTEN induced a G(1) cell cycle arrest specifically in endometrial carcinoma cells that lack endogenous wild-type PTEN. Growth of cells containing wild-type PTEN was unaffected by exogenous PTEN expression. Growth arrest required a functional phosphatase domain but not the PDZ interaction motif of PTEN. Overall levels of CIP/KIP and INK4 family members, the known inhibitory regulators of the G(1) phase of the cell cycle, were unchanged. However, PTEN induced a specific reduction of cyclin D3 levels and an associated increase in the amount of the inhibitor p27(KIP1) complexed with CDK2. Enforced expression of cyclin D3 abrogated the PTEN-induced cell cycle arrest. Although PTEN signaling directly regulates p27(KIP1) levels in some settings, in endometrial carcinoma cells, PTEN expression indirectly regulated p27(KIP1) activity by modulating levels of cyclin D3. These data support multiple mechanisms of PTEN-induced cell cycle arrest.     

PTEN抑癌基因在人胃癌组织中的表达及意义

目的探讨抑癌基因PTEN在胃癌组织中的表达水平及与其生物学行为的关系。方法应用免疫组织化学EnVision法检测116例胃癌组织,35例癌旁异型组织,56例癌旁正常黏膜组织中的PTEN蛋白表达情况。结果胃癌组织中PTEN阳性率为53.4 %(62/116),显著低于异型增生、癌旁正常黏膜组织中的阳性率71.4 %(25/35)、100 %(56/56)(P<0.001)。在各组织学类型中,高中分化腺癌PTEN蛋白阳性表达率最高(72.7 %,32/44),显著高于印戒细胞癌(29.2 %,7/24),P<0.001。PTEN蛋白的表达与淋巴结转移、侵袭程度密切相关(P<0.05)。结论PTEN基因的异常改变与胃癌的发生发展密切相关,可能是胃癌进一步恶化的标志之一,可作为胃癌生物学行为的参考指标,为胃癌的基因治疗提供参考依据。     

PTEN and gastric cancer

The development and progression of gastric cancer is a multi-factor, multi-gene, multi-stage and multi-approach sequential process. PTEN is so far the first discovery of a dual specificity phosphatase activity of the tumor suppressor gene, which regulates the cell cycle and multiple signaling pathways of gastric cancer and plays an important role in the development and progression of gastric cancer. Further studies on PTEN will provide a new way for the early diagnosis, treatment and prognosis of gastric cancer.     

Phosphatase activity of nuclear PTEN is required for CDX2-mediated intestinal differentiation of gastric carcinoma

The PTEN tumor suppressor localizes predominantly to the cytoplasm, where it negatively regulates the phosphatidylinositol 3-kinase-AKT signaling pathway; however, the biological significance of nuclear PTEN in gastric carcinoma (GC) remains unknown. In this study, transduction of recombinant PTEN into GC-derived TMK-1 cells promoted PTEN nuclear localization with increased mRNA levels of CDX2 and intestinal claudins (CLDN3 and CLDN4), whereas the G129E phosphatase 'dead' mutant had no effect. In GC tissue samples, tumors with nuclear PTEN expression frequently demonstrated the intestinal-type claudin phenotype. Our results suggested that nuclear localization of PTEN is important for determining intestinal differentiation of GCs.     

PTEN依赖其磷酸酶活性诱导肝癌细胞发生失巢凋亡机制的探讨

目的 研究抑癌基因PTEN对人肝癌SMMC-7721细胞失巢凋亡的影响并探讨其可能的机制。方法 将携有野生型PTEN基因及无磷酸活性的突变型C124A-PTEN基因的真核表达载体转染SMMC-7721细胞,利用Western印迹杂交法,检测PTEN蛋白表达与蛋白激酶B(PKB／Akt)、焦点黏附激酶(FAK)磷酸化水平的变化,并应用流式细胞仪技术和激光共聚焦显微镜技术,分析各种细胞在黏附与失黏附状态下的凋亡。结果 与对照细胞相比,转染野生型PTEN的SMMC-7721细胞中,FAK和Akt的磷酸化水平分别降低了65．2％和89．1％,且失巢凋亡率由9．5％增至31．3％;而转染C124A-PTEN的SMMC-7721细胞中,FAK和Akt的磷酸化水平及失巢凋亡率均无明显变化。结论 抑癌基因PTEN可依赖其磷酸酶活性抑制FAK和Akt的磷酸化,并诱导肝癌细胞发生失巢调亡。     

Significance of Skp2 expression in human gastric carcinoma and the relationship between Skp2, p27 and PTEN expression

Objective： S-phase kinase-associated protein 2 （Skp2） is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. Its overexpression has been implicated in cell transformation and oncogenesis. In this study, we investigated significance of Skp2 expression in human gastric carcinoma and the relationship between Skp2, p27 and PTEN expression. Methods： Immunohistochemical analysis was performed on 138 surgical resected primary gastric carcinoma specimens, 102 paired metastasis carcinoma tissue specimens in lymph node from the same set of 138 surgical resected primary gastric carcinoma specimens, 30 dysplasia specimens, 30 intestinal metaplasia specimens, and 20 normal gastric mucosa specimens for Skp2 and performed on the same set of 138 surgical resected primary gastric carcinoma specimens for p27 and PTEN. Results： Skp2 labeling frequency % was increased dramatically in intestinal metaplasia, dysplasia, and primary gastric carcinoma compared with normal gastric mucosa （P=0.000, all the same）. Skp2 labeling frequency % in metastasis gastric carcinoma in lymph node was significantly higher than primary gastric carcinoma （P=0.037）. Skp2 labeling frequency % was positively associated with differentiated 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） respectively. An inverse correlation of Skp2 was observed with both its biochemical target p27 expression in gastric carcinoma （rho=-0.451, P=0.000） and with its putative negative regulator, the PTEN tumor suppressor protein （rho=-0.480, P=0.000）. p27 expression had positive relationship with PTEN expression in gastric carcinoma （rho=0.642, P=0.000）. Conclusion： Skp2 overexpression is correlated with carcinogenesis and progression of gastric carcinoma： elevated Skp2 expression is correlated with decreased p27 and PTEN in gastric carcinoma, and p27 expression is parallel with PTEN expression. These suggest that PTEN may regulate expression of p27 through the Skp2 pathway, and the effects of Skp2, p27 and PTEN together play an important role in carcinogenesis and progression of gastric carcinoma.     

Correlation between loss of PTEN expression and Akt phosphorylation in endometrial carcinoma.

The tumor suppressor PTEN acts as a lipid phosphatase, regulates the phosphatidylinositol 3-kinase (PI3K)/Akt-signaling pathway, and modulates cell cycle progression and cell survival. Somatic mutations of PTEN have been reported in a variety of cancers, especially in endometrial carcinoma. To clarify whether and how PTEN and the PI3K/Akt pathway relates to endometrial carcinoma, we examined the expression of those pathway-related proteins in patients with endometrial carcinoma. Of 103 endometrial carcinomas, 37 (36%) showed negative immunohistochemical staining of PTEN. Western blotting revealed that the expression of PTEN in PTEN-negative cases was significantly lower compared with that in positive cases. In contrast, phospho-Akt level in negative cases was significantly higher. We found a significant inverse correlation between PTEN and phospho-Akt (r = -0.796). The expression of phospho-Bad was greater in negative cases, suggesting that Bad might be a target for AKT: The present study demonstrates the phosphorylation of Akt accompanied by the loss of PTEN in clinical specimens of endometrial carcinomas.     

Phosphorylation and inactivation of PTEN at residues Ser380/Thr382/383 induced by Helicobacter pylori promotes gastric epithelial cell survival through PI3K/Akt pathway

Phosphorylation of PTEN at residues Ser380/Thr382/383 leads to loss of phosphatase activity and tumor suppressor function. Here, we found that phosphorylation of PTEN at residues Ser380/Thr382/383 was increased with gastric carcinogenesis, and more importantly, Helicobacter pylori was a trigger of this modification in chronic non-atrophic gastritis. H. pylori could phosphorylate and inactivate PTEN in vivo and in vitro, resulting in survival of gastric epithelial cells. Furthermore, stable expression of dominant-negative mutant PTEN or inhibition of Akt prevented the enhanced survival induced by H. pylori. These results indicate that PTEN phosphorylation at residues Ser380/Thr382/383 is a novel mechanism of PTEN inactivation in gastric carcinogenesis, and H. pylori triggers this modification, resulting in activation of the PI3K/Akt pathway and promotion of cell survival.