Expression of Fas ligand and caspase-3 contributes to formation of immune escape in gastric cancer

AIM: To study the role of Fas ligand (FasL) and Caspase-3 expression in carcinogenesis and progression of gastric cancer and molecular mechanisms of relevant immune escape. METHODS: FasL and Caspase-3 expression was studied in adjacent epithelial cells, cancer cells and lymphocytes of primary foci, and cancer cells of metastatic foci from 113 cases of gastric cancer by streptavidin-biotin-peroxidase(S-P) immunohistochemistry. Expression of both proteins in cancer cells of primary foci was compared with clinicopathological features of gastric cancer. The relationship between Fas L expression in cancer cells and Caspase-3 expression in cancer cells or infiltrating lymphocytes of primary foci was investigated. RESULTS: Cancer cells of primary foci expressed FasL in 53.98 % (61/113) of gastric cancers, more than their adjacent epithelial cells (34.51%, 39/113) (P=0.O03,χ2=8.681), while the expression of Caspase-3 in cancer cells of primary foci was detected in 32.74 % (37/113) of gastric cancers, less than in the adjacent epithelial cells (50.44 %, 57/113)(P=0.O07, χ2=7.286). Infiltrating lymphocytes of the primary foci showed positive immunoreactivity to Caspase-3 in70.80 % (80/113) of gastric cancers, more than their corresponding adjacent epithelial cells (P=0.O01, χ2=10.635) or cancer cells of primary loci (P=-O.O00, χ2=32.767). FasL was less expressed in cancer cells of metastases (51.16 %,22/43) than in those of the corresponding primary foci( 81.58 %, 31/38) (P=0.O03, χ2=9.907). Conversely, Caspase-3 was more expressed in cancer cells of metastases(58.14 %, 25/43) than in those of the corresponding primary foci (34.21%, 13/38) (P=0.031, χ2=4.638). FasL expression was significantly correlated with tumor size (P=0.035,rs=0.276), invasive depth (P=0.039, rs=0.195), metastasis(P=0.039, rs=0.195), differentiation (P=0.015, rs=0.228)and Lauren‘‘s classification (P=0.038, rs=0. 196), but not with age or gender of patients, growth pattern or TNM staging of gastric cancer (P>0.05). In contrast, Caspase-3 expression showed no correlation with any dinicopathological parametersdescribed above in cancer cells of the primary foci (p>0.05).Interestingly, FasL expression in primary gastric cancer cells paralleled to Caspase-3 expression in infiltrating lymphocytes of the primary foci (P=0.016, χ2=5.825).CONCLUSION: Up-regulated expression of FasL and downregulated expression of Caspase-3 in cancer cells of primary foci play an important role in gastric carcinogenesis. As an effective marker to reveal the biological behaviors, FasL is implicated in differentiation, growth, invasion and metastasis of gastric cancer by inducing apoptosis of infiltrating lymphocytes. Chemical substances derived from bhe primary foci and metastatic microenvironment can inhibit t~e growth of metastatic cells by enhancing Caspase-3 expression and diminishing FasL expression.     

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.     

胃癌组织中PTEN,MMP-9和Caspase-3表达的关系

目的:研究PTEN,MMP-9和Caspase-3在胃癌及正常胃组织中的表达,探讨他们在胃癌的发生、发展、浸润和转移中的作用．方法:选择临床病理资料齐全的胃癌蜡块标本54例,另取正常胃黏膜标本15例作对照．采用SP免疫组化方法检测PTEN,MMP-9和 Caspase-3在其中的表达．结果:胃癌中PTEN低表达(28/54,51．9％),且肿瘤浸润深(P=0．004)、有淋巴(P=0．003) 和远隔转移(P=0．01 5)、临床分期高(P= 0．001)、病理分化低(P=0．008)时降低．胃癌中MMP-9高表达(41／54,75．9％),且肿瘤浸润深(P=0．040)、有淋巴转移(P=0．025)、临床分期高(P=0．039)、病理分化低(P=0．009)时增高．胃癌中Caspase-3低表达(12／54,22．2％), 且有淋巴转移(P=0．045)、临床分期高(P= 0．015)、病理分化低(P=0．035)时降低．胃癌中PTEN与MMP-9(r=-0．543,P=0．001), Caspase-3与MMP-9的表达负相关(r=0．741, P=0.001),PTEN与Caspase-3的表达正相关(r =0．515,P=0．001)．结论:胃癌中PTEN,Caspase-3低表达,MMP-9 高表达;PTEN、MMP-9和Caspase-3可作为胃癌诊断和预后判断的指标．     

老年贲门癌组织中caspase-3表达及其临床意义

目的研究半胱氨酸天冬氨酸蛋白酶3(caspase-3)表达在老年贲门癌发生发展中的作用。方法采用免疫组化S-P法观察113例老年贲门癌旁上皮细胞、原发癌细胞和浸润淋巴细胞以及转移灶癌细胞中caspase-3表达,并分析原发灶癌细胞caspase-3表达与贲门癌临床病理特征的关系。结果caspase-3在贲门癌旁上皮细胞中的表达高于原发灶癌细胞(P<0·05);caspase-3在贲门癌原发灶浸润淋巴细胞中的阳性率高于贲门癌旁上皮细胞和原发灶癌细胞(P<0·05);转移灶癌细胞中caspase-3阳性率高于原发灶癌细胞(P<0·05);原发灶癌细胞中caspase-3表达与贲门癌患者的年龄、性别以及贲门癌肿瘤大小、浸润深度、转移、TNM分期、生长方式和分化程度无相关性(P<0·05)。结论贲门癌原发灶癌细胞caspase-3表达下调和浸润淋巴细胞caspase-3表达上调与贲门癌发生有关,来自原发灶和转移微环境中的化学物质可能通过提高转移灶癌细胞中caspase-3表达,进而起到抑制转移灶的作用。     

胃癌组织中MTA1,PTEN,E-cadherin的表达及其相互关系

目的:观察MTA1,PTEN,E-cadherin蛋白在胃癌和正常胃黏膜组织中的表达,探讨其与胃癌浸润、转移和生物学行为的关系.方法:应用免疫组织化学方法检测54例胃癌手术切除标本和15例正常胃黏膜组织中MTA1,PTEN,E-cadherin的表达.各指标之间相关因素的差异性比较采用χ2检验,相关性研究采用Spearman相关分析:结果:与正常胃组织相比,MTA1蛋白在胃癌组织中高表达(46.3% vs 6.7%,P＜0.01),PTEN和E-cadherin蛋白在胃癌组织中表达下调或缺失(51.9% vs 100%,42.6% vs 100%,均P＜0.01).MTA1和PTEN的阳性表达率与肿瘤浸润深度(P=0.003,P=0.001)、病理分期(P=0.004,P=0.008)、淋巴转移(P=0.000,P=0.001)、远隔转移(P=0.004,P=0.006)、临床分期有关(P=0.001,P=0.000);E-cadherin的正常表达率与肿瘤浸润深度(P=0.027)、病理分化程度(P=0.006)、淋巴转移(P=0.044)、临床分期有关(P=0.000).Spearman相关分析显MTA1与PTEN蛋白、MTA1与E-cadherin蛋白的表达呈负相关(r=-0.518,r=-0.424,均p＜0.05).PTEN蛋白与E-cadherin蛋白的表达呈正相关(r=0.53,P＜0.05).结论:MTA1蛋白水平高表达和PTEN,E-cadherin蛋白水平低表达可能与胃癌浸润和转移有关,且联合检测可以用于判断胃癌的生物学行为.     

miR-1180在胃癌中的表达及其对胃癌增殖、凋亡的影响

目的研究miR-1180在胃腺癌组织及胃癌细胞系中的表达及其对胃癌细胞增殖、凋亡的影响,探讨miR-1180在胃癌中可能的作用机制。方法应用qRT-PCR检测58例胃腺癌及20例癌旁正常组织中miR-1180的表达,分析其表达与胃腺癌临床病理特征的关系。检测miR-1180在胃癌细胞系中的表达,慢病毒干扰技术下调SGC-7901中miR-1180的表达,检测下调后对SGC-7901增殖、凋亡及细胞周期的影响。结果与癌旁正常组织比较,58例胃腺癌组织中miR-1180的表达明显增加(t=16.463,P=0.000),miR-1180的表达与患者的肿瘤大小、TNM分期及淋巴结转移有关(P均<0.05)。miR-1180在胃癌细胞系中表达升高(P=0.000),下调SGC-7901中miR-1180的表达,可见细胞增殖减少(3113±74 vs 1673±51,P=0.000),凋亡增加(4.313±0.220 vs 7.717±0.125,P=0.000);细胞周期G 1期细胞明显增加(45.89±0.33 vs 60.44±0.390,P=0.000),S期细胞明显减少(35.523±0.354 vs 21.953±0.444,P=0.000),G 2期细胞变化不大(18.587±0.672 vs 17.603±0.731,P=0.162)。结论miR-1180的表达促进胃癌的进展,胃癌中miR-1180的高表达与预后不良有关。     

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.     

Maspin expression and its clinicopathological significance in tumorigenesis and progression of gastric cancer

AIM:To investigate maspin expression in tumorigenesis and progression of gastric cancer and to explore its relevant molecular mechanisms.METHODS:Formalin-fixed and paraffin-embedded tissues from normal mucosa (n=182), dysplasia (n=69), cancer (n=l13) of the stomach were studied for maspin expression by immunohistochemistry. Microvessel density (MVD) in gastric cancer was labeled using anti-CD34 antibody. Maspin expression was compared with clinical parameters and MVD of tumors. Caspase-3 expression was also detected in gastric carcinoma by immunohistochemistry. The relationship between Caspase-3 and maspin expression was concerned as well.RESULTS:The positive rates of maspin expression were 79.8% (145/182), 75.4%(52/69) and 50.4%(57/113) in normal mucosa, dysplasia and cancer of the stomach,respectively.Cancer less frequently expressed maspin than normal mucosa and dysplasia (P&lt;0.05).Maspin expression showed a significantly negative association with invasive depth, metastasis, Lauren‘s and Nakamura‘s classification (P&lt;0.05),but not with tumor size, Borrmann‘s classification,growth pattern or TNIVl staging (P&gt;0.05). The positive rate of Caspase-3 was significantly lower in gastric cancer than in normal gastric mucosa (P&lt;0.05,32.7% vs 50.4%). It was noteworthy that maspin expression was negatively correlated with MVD, but positively correlated with expression of Caspase-3 in gastric cancer (P&lt;0.05).CONCLUSION:Down-regulated maspin expression is a late molecular event in gastric carcinogenesis. Reduced expression of maspin contributes to progression of gastric cancer probably by inhibiting cell adhesion, enhandng cell mobility,decreasing cell apoptosis and facilitating angiogenesis.Additionally altered expression of maspin underlies the molecular mechanism of differentiation of gastric cancer and supports the different histogenetic pathways of intestinal and diffuse gastric cancers. Maspin expression can be considered as an effective and objective marker to reveal biological behaviors of gastric cancer.     

Pathobiological significance of vascular endothelial growth factor and Maspin expressions in human gastric carcinoma

AIM: To investigate the correlation between expression of vascular endothelial growth factor (VEGF) and cell differentiation, invasion, metastasis and Maspin expression in gastric carcinoma.METHODS: Formalin-fixed paraffin-embedded tissue specimens from 73 cases of gastric carcinoma were studied with SP immunohistochemistry, using anti-VEGF monoclonal antibody, and thirty-nine of them were studied using antiMaspin monoclonal antibody. VEGF expression was compared with the clinical stage, lymph node metastasis, and Borrmann‘s and WHO‘s classification of gastric carcinoma.RESULTS: The positive rate of VEGF expression was significantly higher in adjacent non-carcinoma epithelia (ANCE) than in non-metaplastic, non-carcinoma gastric epithelia (NMNCE), which were at least 4 cm distant from the primary tumor (P = 0.000, x^2= 73.03). The positive rate of VEGF expression was significantly higher in advanced gastric carcinoma (AGC) than in early gastric carcinoma (EGC) (P = 0.032, x^2 = 4.62). The positive rate of VEGF expression in gastric carcinomas with lymph node metastases was significantly higher than that in those without metastasis (P = 0.006, x^2 = 7.47). Maspin was weakly expressed in 16 out of 39 cases of NMNCE, and the positive immunoreaction was limited to gland cells of the stomach body. There was no significant correlation between the expression of VEGF and histological or gross classifications, and correlation between the expressions of VEGF and Maspin in gastric carcinoma (P = 0.648, x^2 = 0.21).CONCLUSION: Expression of VEGF is significantly correlated to the malignant biological behaviors of gastric carcinoma,but there is no significant correlation between the expression of VEGF and Maspin.     

Tnactivation of PTEN is associated with increased angiogenesis and VEGF overexpression in gastric cancer

AIM: To investigate the expression of PTEN/MMAC1/TEP1and vascular endothelial growth factor (VEGF), their roles in biologic behavior and angiogenesis and their association in gastric cancer.METHODS: Immunohistochemical staining was used to evaluate the expression of PTEN, VEGF and microvascular density (MVD) on paraffin-embedded sections in 70 patients with primary gastric cancer and 24 patients with chronic superficial gastritis (CSG). Expression of PTEN, VEGF and MVD were compared with clinicopathological features of gastric cancer. The relationship between expression of PTEN, VEGF and MVD as well as the relationship between PTEN and VEGF expression in caner cells were investigated.RESULTS: PTEN expression significantly decreased (t= 3.98,P＜0.01) whereas both VEGF expression and MVD significant increased (t = 4.29 and 4.41, respectively, both P＜0.01)in gastric cancer group compared with CSG group. PTEN expression was significantly down-regulated (t = 1.95,P＜0.05) whereas VEGF expression (t = 2.37, P＜0.05) and MVD (t = 3.28, P＜0.01) was significantly up-regulated in advanced gastric cancer compared with early-stage gastric cancer. PTEN expression in gastric cancer showed a negative association with lymph node metastasis (t= 3.91, P＜0.01),invasion depth (t= 1.95, P＜0.05) and age (t= 4.69, P＜0.01).MVD in PTEN-negative gastric cancer was significantly higher than that in PTEN-positive gastric cancer (t = 3.69,P＜0.01), and there was a negative correlation between PTEN expression and MVD (γ = -0.363, P＜0.05). VEGF expression was positively associated with invasion depth (especially with serosa invasion, t = 4.69, P＜0.01), lymph node metastasis (t= 2.31, P＜0.05) and TNM stage (t= 3.04,P＜0.01). MVD in VEGF-positive gastric cancer was significantly higher than that in VEGF-negative gastric cancer (t = 4.62,P＜0.01), and there was a positive correlation between VEGF expression of and MVD (γ = 0.512, P＜0.05). VEGF expression in PTEN-negative gastric cancer was significantly stronger than that in PTEN-positive gastric cancer (t = 2.61,P＜0.05), and there was a significantly negative correlation between the expression of VEGF and PTEN (γ = -0.403,P＜0.05).CONCLUSION: Our results imply that inactivation of PTEN gene and over-expression of VEGF contribute to the neovascularization and progression of gastric cancer. PTENrelated angiogenesis might be attributed to its up-regulation of VEGF expression. PTEN and VEGF could be used as the markers reflecting the biologic behaviors of tumor and viable targets in therapeutic approaches to inhibit angiogenesis of gastric cancers.     

Expression of PTEN, PPM1A and P-Smad2 in hepatocellular carcinomas and adjacent liver tissues

AIM: To investigate the expressions of PTEN, PPM1A and P-Smad2 in hepatocellular carcinoma (HCC) and their significance. METHODS: The expressions of PTEN, PPM1A and P-Smad2 in 31 HCC tissues, 25 adjacent liver tissues and 13 non-tumor liver tissues were detected by using Envision immunohistochemical technique. RESULTS: The positive expression (64.52%) and staining intensity (4.19 ± 3.31) of PTEN in the cytoplasm of HCC were significantly lower and weaker than those in the adjacent or non-tumor liver tissues (97.37%, 7.88 ± 0.93; 100%, 7.77 ± 0.93, respectively) (P < 0.05), and its staining intensity in the cytoplasm of HCC, which belongs to Edmondson pathologic grades Ⅱ-Ⅲ and above, was also lower than that of gradeⅠandⅠ-Ⅱ. Furthermore, its location in the nucleus or cytoplasm of liver cells was negatively correlated with the progression of liver disease (r = -0.339, P = 0.002); most of PPM1A might be only expressed in the nucleus of adjacent liver tissues, non-HCC tissues or Edmondson gradeⅠandⅠ-Ⅱ HCC, but it was mainly expressed in the cytoplasm of HCC with Edmondson grade ≥Ⅱ, weakly or negatively expressed in the nucleus (P < 0.05), and its location was negatively correlated with the progression of liver disease (r = -0.45, P = 0.0000). P-Smad2, which was mostly located in the nucleus and cytoplasm of gradeⅠ andⅠ-Ⅱ HCC, surrounding or non-tumor liver tissues, was only in the nucleus of HCC with Edmondson grade Ⅱ and above (P < 0.001), and its location was positively correlated with the disease progression (r = 0.224, P = 0.016). Spearman correlation analysis revealed that P-Smad2 was significantly negatively correlated with PTEN and PPM1A (r = -0.748, P = 0.000; r = -0.366, P = 0.001, respectively); and PTEN and PPM1A were positively correlated with HCC carcinogenesis (r = 0.428, P = 0.000). CONCLUSION: The aberrant location of expression and staining intensity of PTEN, PPM1A and P-Smad2 in HCC and their relationship might have an impact on the pathogenesis of HCC.     

Inactivation of PTEN is associated with increased angiogenesis and VEGF overexpression in gastric cancer

AIM: To investigate the expression of PTEN/MMAC1/TEP1 and vascular endothelial growth factor (VEGF), their roles in biologic behavior and angiogenesis and their association in gastric cancer.METHODS: Immunohistochemical staining was used to evaluate the expression of PTEN, VEGF and microvascular density (MVD) on paraffin-embedded sections in 70 patients with primary gastric cancer and 24 patients with chronic superficial gastritis (CSG). Expression of PTEN, VEGF and MVD were compared with clinicopathological features of gastric cancer. The relationship between expression of PTEN, VEGF and MVD as well as the relationship between PTEN and VEGF expression in caner cells were investigated. RESULTS: PTEN expression significantly decreased (t= 3.98, P&lt;0.01) whereas both VEGF expression and MVD significant increased (t = 4.29 and 4.41, respectively, both P&lt;0.01) in gastric cancer group compared with CSG group. PTEN expression was significantly down-regulated (t=1.95, P&lt;0.05) whereas VEGF expression (t = 2.37, P&lt;0.05) and MVD (t= 3.28, P&lt;0.01) was significantly up-regulated in advanced gastric cancer compared with early-stage gastric cancer. PTEN expression in gastric cancer showed a negative association with lymph node metastasis (t= 3.91, P&lt;0.01), invasion depth (t= 1.95, P&lt;0.05) and age (t= 4.69, P&lt;0.01). MVD in PTEN-negative gastric cancer was significantly higher than that in PTEN-positive gastric cancer (t=3.69, P&lt;0.01), and there was a negative correlation betweenPTEN expression and MVD (γ=-0.363, P&lt;0.05). VEGF expression was positively associated with invasion depth (especially with serosa invasion, t = 4.69, P&lt;0.01), lymph node metastasis (t= 2.31, P&lt;0.05) and TNM stage (t= 3.04, P&lt;0.01). MVD in VEGF-positive gaslyic cancer was significantly higher than that in VEGF-negative gastric cancer (t=4.62, P&lt;0.01), and there was a positive correlation between VEGF expression of and MVD (y = 0.512, P&lt;0.05). VEGF expression in PTEN-negative gaslyic cancer was significantly stronger than that in PTEN-positive gastric cancer (t=2.61, P&lt;0.05), and there was a significantly negative correlation between the expression of VEGF and PTEN (γ=-0.403, P&lt;0.05).CONCLUSION: Our results imply that inactivation of PTEN gene and over-expression of VEGF contribute to the neovascularization and progression of gastric cancer. PTEN-related angiogenesis might be attributed to its up-regulation of VEGF expression. PTEN and VEGF could be used as the markers reflecting the biologic behaviors of tumor and viable targets in therapeutic approaches to inhibit angiogenesis of gastric cancers.     

胃癌组织中Survivin、PTEN、P53基因的表达及意义

目的　探讨凋亡抑制基因 Survivin和抑癌基因 PTEN、P53在胃癌组织中的表达及其与胃癌发生发展、临床病理特征之间的关系。方法　应用免疫组织化学链霉亲和素方法 (SABC) ,检测 Survivin、PTEN和 P53基因在 6 5例胃癌、2 6例不典型增生胃黏膜、10例浅表性胃炎和 30例正常胃黏膜组织中的表达。结果　胃癌组织中Survivin、PTEN、突变型 P53基因的阳性表达率分别为 70 %、4 8%、6 5 % ,不典型增生胃黏膜中分别为 4 2 %、85 %、31% ,Survivin和突变型 P53基因在正常胃黏膜和浅表性胃炎组织中不表达 ,PTEN基因在正常胃黏膜和浅表性胃炎组织中全部呈阳性表达。胃癌组织中 PTEN基因的表达与正常胃黏膜组织中的表达差异有显著性 (P<0 .0 5 ) ,胃癌组织、不典型增生胃黏膜以及正常胃黏膜中 Survivin和突变型 P53基因的表达差异均有显著性 (P<0 .0 5 )。随临床分期增加、胃癌分化程度降低、浸润深度加深、淋巴结的转移 ,突变型 P53基因的阳性表达率逐渐上升 (P<0 .0 5 ) ,PTEN基因的阳性表达率逐渐降低 (P<0 .0 5 )。在胃癌组织中 Survivin与突变型 P53基因的表达呈正相关 (P<0 .0 5 ) ,与 PTEN基因的表达呈负相关 (P<0 .0 5 ) ,PTEN基因与突变型 P53基因的表达呈负相关 (P<0 .0 5 )。结论　 Survivin、PTEN和 P53     

基质金属蛋白酶-9、血管内皮生长因子和增殖细胞核抗原在胃腺癌表达的相关性及临床意义

目的 研究胃腺癌中基质金属蛋白酶-9(MMP-9)及其相关因子血管内皮生长因子(VEGF)和增殖细胞核抗原(PCNA)蛋白的表达,并分析其临床意义.方法 利用组织芯片技术,通过免疫组化法检测45例胃腺癌组织及其相应的45例癌旁组织和10例正常胃黏膜组织中MMP-9、VEGF和PCNA蛋白的表达,并分析它们的相关性及其与胃腺癌的分化程度和发生发展的关系.结果 本研究中MMP-9、VEGF和PCNA分别在胃腺癌、癌旁组织、正常胃黏膜中检出的阳性率为:MMP-9,82.2%(37/45)、64.4%(29/45)、30.0%(3/10),差异有统计学意义(P=0.019);VEGF,73.3%(33/45)、62.2%(28/45)、30.0%(3/10),差异有统计学意义(P=0.029);PCNA,84.4%(38/45)、71.1%(32/45)、10.0%(1/10),差异有统计学意义(P=0.001).MMP-9、VEGF和PCNA分别在高、中、低分化胃腺癌组织中的阳性率为:MMP-9,70.0%(7/10)、80.0%(8/10)、88.0%(22/25),差异有统计学意义(P=0.015);VEGF,50.0%(5/10)、60.0%(6/10)、88.0%(22/25),差异有统计学意义(P=0.000);PCNA,60.0%(6/10)、90.0%(9/10)、92.0%(23/25),差异有统计学意义(P=0.004).等级相关分析表明MMP-9、VEGF和PCNA呈两两正相关(P<0.05).结论 组织芯片技术是胃腺癌中各种蛋白表达的一种强有力的分析工具.MMP-9、VEGF和PCNA蛋白参与胃腺癌的发生发展过程,可以成为临床上评价预后的指标.     

STAT5信号转导通路及其靶基因产物与结直肠癌恶性潜能的关系

目的:分析STAT5及其靶基因产物Cyclin D1与Caspase-3在结直肠癌组织中的表达情况,探讨STAT5及其靶基因产物在结直肠癌发病机制中的作用.方法:收集北京海淀医院外科2003-12/ 2005-12经手术切除的结直肠癌标本60例,应用Western blot检测60例结直肠癌组织、正常黏膜中STAT5及其靶基因产物Cyclin D1与Caspase-3表达.结果:p-STAT5,Cyclin D1及Caspase-3表达水平在结直肠癌组织中明显高于正常黏膜(P= 0.028,0.035,0.046);p-STAT5表达水平与分期相关(P=0.026);Caspase-3与分期相关(P= 0.041).p-STAT5与Caspase-3在结直肠癌组织中表达情况呈线性相关(r=0.412,P<0.05).结论:STAT5信号转导通路可能在结直肠癌发生过程中起重要作用,检测结直肠癌中STAT5及其靶基因产物的表达可以反映肿瘤的恶性潜能.     

Correlative studies on uPA mRNA and uPAR mRNA expression with vascular endothelial growth factor, microvessel density, progression and survival time of patients with gastric cancer

AIM: TO investigate the correlations between the expression of urokinase-type plasminogen activator (uPA) mRNA, uPA receptor (uPAR) mRNA and vascular endothelial growth factor (VEGF) protein and clinicopathologic features, microvessel density (MVD) and survival time. METHODS: In situ hybridization and immuno-histochemistry techniques were used to study the expressions of uPA mRNA, uPAR mRNA, VEGF and CD34 protein in 105 gastric carcinoma specimens. RESULTS: Expressions of uPA mRNA, uPAR mRNA and VEGF protein were observed in 61 (58.1%) cases, 70 (66.7%) cases and 67 (63.8%) cases, respectively. The uPA mRNA and uPAR mRNA positive expression rates in infiltrating-type cases (73.7%, 75.4%), stageⅢ-Ⅳ(72.1%, 75.4%), vessel invasion (63.2%, 69.9%), lymphatic metastasis (67.1%, 74.4%) and distant metastasis (88.1%, 85.7%) were significantly higher than those of the expanding-type (X2= 15.57, P= 0.001; X2=6.91, P=0.046), stageⅠ-Ⅱ(X2 = 19.22, P = 0.001; X2= 16.75, P= 0.001), non-vessel invasion (X2 = 11.92, P = 0.006; X2 = 14.15, P = 0.002), non-lymphatic metastasis (X2 = 28.41, P = 0.001; X2= 22.5, P=0.005) and non-distant metastasis (X2 = 12.32, P= 0.004; X2= 17.42, P = 0.002; X2 = 11.25, P = 0.012; X2 = 18.12, P = 0.002).The VEGF positive expression rates in infiltrating-type cases (75.4%), stageⅢ-Ⅳ(88.5%), vessel invasion (82.9%), lymphatic metastasis (84.3%) and distant metastasis (95.2%) were significantly higher than those of the expanding-type (X2 = 9.61, P = 0.021), stage I-II (X2=16.66, P = 0.001), non-vessel invasion (X2= 29.38, P = 0.001), non-lymphatic metastasis (X2 = 18.68, P = 0.005), and non-distant metastasis (X2= 22.72, P = 0.007; X2 = 21.62, P = 0.004). The mean MVD in the specimens positive for the uPA mRNA, uPAR mRNA and VEGF protein was markedly higher than those with negative expression groups. Moreover, a positive relation between MVD and uPA mRNA (rs = 0.199, P = 0.042), uPAR mRNA (rs = 0.278, P = 0.035), and VEGF (rs = 0.398, P = 0.048) expressions was observed. The mean survival time in cases with positive uPA mRNA, uPAR mRNA and VEGF protein expression or MVD value≥54.9 was significantly shorter than those in cases with negative expression or MVD value < 54.9. CONCLUSION: uPA and uPAR expressions are correlated with enhanced VEGF-induced tumor angiogenesis and may play a role in invasion and nodal metastasis of gastric carcinoma, thereby serving as prognostic markers of gastric cancer.     

CDw75 is a significant histopathological marker for gastric carcinoma

AIM: To study the expression of CDw75 in patients with gastric carcinoma and to correlate CDw75 expression with progression of the tumor. METHODS: Immunohistochemical method was used to examine the expression of CDw75 in 72 cases of the gastric carcinoma and adjacent normal gastric mucosa, and the percentage of the cells positively stained with CDw75 was calculated using a computer-aided microscopic image analysis system. RESULTS: CDw75 was not expressed in normal gastric mucosa but detected in 37 of the 72 neoplastic gastric lesions. The expression of CDw75 was associated with the tumor progression as indicated by its close correlation with the depth of the tumor infiltration (chi(2)=18.415, P<0.01), TNM stage (chi(2)=10.419, P<0.05) and lymph node metastasis (chi(2)=6.675, P<0.01). The overall survival rate of the patients with positive CDw75 expression (32.4%) was significantly lower than that of the patients without CDw75 expression (71.4%) (P<0.01). There was no significant correlation between the expression of CDw75 and the sex and age and histological type of patients (P>0.05). CONCLUSION: These findings suggest that the expression of CDw75 is a significant histopathological marker for more advanced stage of gastric carcinoma and indicates a poor prognosis for the patients.     

p53异构体和MDM2、PTEN在胃癌组织中表达的相关性

目的探讨p53的选择性剪接异构体与双微基因2(MDM2)、同源性磷酸酶张力蛋白(PTEN)在胃癌组织中的表达及其相关性。方法分别应用巢式逆转录多聚酶链反应(NT-PCR)和免疫组织化学(PV-9000两步法)方法检测p53的五种选择性剪接异构体和MDM2、PTEN在胃癌组织和癌旁胃组织中的表达,并进行统计学分析。结果在30例胃癌患者癌组织和癌旁胃组织中均未检测到三种p53异构体p53γ、Δ133p53β、Δ133p53γ的mRNA表达。与癌旁组织比较,胃癌组织中Δ133p53表达阳性率高,p53β表达阳性率低,MDM2蛋白表达阳性率高,PTEN蛋白表达阳性率低(P均<0.01)。Spearman’s相关性分析显示,Δ133p53和MDM2,p53β和PTEN在胃癌中表达均呈正相关关系(r=0.408,P=0.025;r=0.413,P=0.02);Δ133p53和PTEN,p53β和MDM2在胃癌中表达呈负相关关系(r=-0.467,P=0.009;r=-0.480,P=0.007)。结论Δ133p53、p53β通过调节p53活性,并以p53为中介,影响了PTEN-MDM2-p53网络环路中PTEN、MDM2蛋白的表达。     

Significance of Survivin and PTEN expression in full lymph node-examined gastric cancer

AIM:To study the relationship between Survivin andPTEN expression and lymph node metastasis,depth ofinvasion and prognosis of gastric cancer patients in Chi-na.METHODS:Specimens of gastric cancer tissue were col-lected from the Affiliated Hospital of Jianghan University.All the 140 patients had complete examination data.Alllymph nodes were found by the fat-clearing method.Theinterrupted serial 4-micron sections,routine hematoxylinand eosin staining and immunohistochemical methodswere used to detect the lymph node metastases.Gastriccancer tissue microarray was performed to test the ex-pression of Survivin and PTEN(17A)in gastric cancer byimmunohistochemical method.All data were processedusing x~2 test,Fisher's exact test,Kaplan-Meyer Log-rankmethod and Cox multivariate analysis(SPSS 12.0 soft-ware).RESULTS:One hundred and eighteen specimenswere used in our tissue microarray(utilization rate was82.4%).A total of 7580 lymph nodes were found.Metas-tases were found in 90 specimens and 1618 lymph nodeswere detected.The positive rate of Survivin and PTENexpression was 52.5%(62/118)and 76.2%(90/118),respectively.A highly positive correlation was found be-tween Survivin and PTEN expression(x~2=4.17,P=0.04).Survivin expression was positively correlated with UICCN stage(x~2=8.69,P=0.03)and histological classifica- tion(x~2=4.41,P=0.04)by x~2 tests.PTEN expression waspositively correlated with depth of invasion(P=0.02)andhistological classification(x~2=5.47,P=0.02).But Survivinand PTEN expressions were not related with prognosis ofgastric cancer patients.A significant correlation betweenlymph node metastasis and prognosis was demonstratedby Cox multivariate analysis(x~2=4.85,P=0.028).CONCLUSION:Survivin is positively correlated withPTEN expression in gastric cancer and is a molecularmarker of lymph node metastasis while PTEN expressionis a molecular marker of advanced gastric cancer.UICCN stage is the most important prognostic factor of gastriccancer in China.     

Up-regulation of PIK3CA promotes metastasis in gastric carcinoma

AIM:To explore expressions of PIK3CA in the progression of gastric cancer from primary to metastasis and its effects on activation of phosphatidylinositol 3-kinase(PI3K)/Akt pathway.METHODS:mRNA and protein levels of PIK3CA were assessed,respectively,by real-time quantitative polymerase chain reaction and immunohistochemistry in specimens of normal gastric mucosa,primary foci and lymph node and distant metastasis of gastric cancer.Akt and phosphorylated Akt protein were also examined by Western blotting in these tissues,in order to analyze the effect of PIK3CA expression level changes on the activation of PI3K/Akt signaling pathway.RESULTS:PIK3CA mRNA in lymph node metastasis were approximately 5 and 2 folds higher,respectively,than that in the corresponding normal gastric mucosa and primary gastric cancer tissues(P<0.05),while no statistical significance was found compared with distant metastasis.Immunohistochemically,PIK3CA protein expression was discovered in 7(35%)specimens of 20 primary foci vs 10(67%)of 15 of lymph node metastasis or 11(61%)of 18 of distant metastasis(35%vs 67%,P=0.015;35%vs 61%,P=0.044).With the increased level of PIK3CA expression,the total Akt protein expression remained almost unchanged,but p-Akt protein was upregulated markedly.CONCLUSION:Increased expression of PIK3CA is expected to be a promising indicator of metastasis in gastric cancer.Up-regulation of PIK3CA may promote the metastasis of gastric cancer through aberrant activation of PI3K/Akt signaling.