胃癌前病变和胃癌组织中TGBβ_1、TGFβRⅡ和Smad4蛋白表达的研究
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摘要
目的：观察胃癌前病变（肠上皮化生IM、不典型增生Dys）和胃癌（GC）组织中TGF-β1、TGF-βRⅡ和Smad4蛋白表达水平变化及其与临床病理指标之间的关系，探讨TGF-β信号转导通路中TGF-β1、TGF-βRⅡ和Smad4在胃癌发生发展中的作用以及三者间的相互关系。
方法：选择经胃镜活检病理组织学证实的肠上皮化生（IM）者20例、不典型增生（Dys）者20例及胃癌患者46例为试验组，其中胃癌患者全部手术。据病理和手术探查结果将46例胃癌按肿瘤组织学分化程度分为高中分化组（乳头状腺癌、管状腺癌，22例）和低分化组（低分化腺癌、印戒细胞癌，24例）；按有无区域淋巴结转移分为淋巴结转移组（25例）和无淋巴结转移组（21例）；按有无远处转移分为远处转移组（10例）和无远处转移组（36例）；按浸润深度分为累及浆膜组（24例）和未及浆膜组（22例）；按TNM分期（1988年国际抗癌联盟统一方案）分为TNMⅠ、Ⅱ期组（19例）和TNM Ⅲ、Ⅳ期组（27例）。另选20例胃镜观察及活检病理组织学基本正常者为对照组。所有入选者均排除心、脑、肝、肾、肠、胰腺等疾患。测试者均于行
胃镜检查时取胃黏膜标本5块（胃窦2块、胃体2块、胃角1块），标本足够大，深达黏膜肌。10％中性福尔马林固定4小时以上，石蜡包埋，连续切片，片厚5μm。常规HE染色，光镜下确定病理组织学类型。每例标本行免疫组化SABC法检测TGF-β1、TGF-βRⅡ、Smad4蛋白表达水平，病理图象分析系统处理切片染色结果。
结果：1.免疫组化染色显示：TGF-β1的阳性反应物位于胞浆内，在正常胃黏膜，TGF-β1阳性细胞较少，着色均匀，主要分布于黏膜表层；癌组织中，TGF-β1在胞浆内着色不均，呈棕褐色，颗粒状。TGF-βRⅡ的阳性反应物位于胞浆和（或）胞膜，在正常胃黏膜，TGF-βRⅡ呈弥漫或颗粒状染色；癌组织中TGF-βRⅡ表达较正常组织明显减弱甚至无表达。Smad4蛋白阳性反应物位于胞浆和（或）胞核，在正常胃黏膜，Smad4蛋白在胞浆和胞核中均有染色；胃癌细胞内，Smad4蛋白阳性染色较正常组织明显减弱甚至缺失，且阳性细胞胞核染色罕见。2. TGF-β1、TGF-βRⅡ和Smad4蛋白在各组中的表达水平变化：GC组TGF-β1蛋白表达水平（阳性面积％ 下同）为64.62±14.71，显著高于NC组（18.97±10.86，P<0.01）、IM组（24.42±13.45， P<0.01）和Dys组（33.60±14.61，P<0.01）；Dys组与NC间也有明显差异（P<0.05）；IM组与NC组间无明显差异（P＞0.05）。GC组TGF-βRⅡ表达水平为17.91
±10.66，显著低于NC组（61.94±12.64，P<0.01）、IM组（58.07±11.14，P<0.01）和Dys组（53.35±14.71，P<0.01）；IM组与NC组、Dys组与NC组间差异无显著性（P＞0.05，P＞0.05）。GC组Smad4蛋白表达水平为23.57±14.31，显著低于NC组（70.33±12.13，P<0.01）、IM组（67.93±13.93，P<0.01）和Dys组（68.82±13.22，P<0.01）；IM组与NC组、Dys组与NC组间差异无显著性（P＞0.05，P＞0.05）。3. GC组TGF-β1、TGF-βRⅡ和Smad4蛋白表达与临床病理的关系：胃癌组织学分化程度：低分化组中TGF-β1表达水平（71.29±10.05）显著高于高中分化组（57.33±15.70,P<0.01）；TGF-βRⅡ和Smad4蛋白表达水平(14.09±9.63,16.64±12.81)显著低于高中分化组（22.08±10.35, P<0.01；30.22±12.20, P<0.01）。区域淋巴结转移：有区域淋巴结转移组TGF-β1表达水平（72.30±7.57）显著高于无区域淋巴结转移组（55.47±16.02,P<0.01）； TGF-βRⅡ表达水平(14.82±10.78)显著低于无区域淋巴结转移组（21.59±9.50,P<0.01）；Smad4蛋白表达水平在两组间差异无显著性（P>0.05）。 远处转移：远处转移组Smad4蛋白表达水平（14.95±7.22）显著低于无远处转移组（27.08±12.32,P<0.01）；TGF-β1和TGF-βRⅡ表达水平在两组间差异无显著性（P>0.05）。浸润深度：累及浆膜组TGF-β1表达水平（68.73±12.55）明显高于未及浆膜组（60.13±15.84,P<0.05）；Smad4蛋
白表达水平（14.81±9.33）明显低于未及浆膜组（25.67±13.85,P<0.05）；TGF-βRⅡ表达水平在两组间差异无显著性（P＞0.05）。TNM分期：Ⅲ、Ⅳ期组TGF-β1表达水平（71.13±9.75）显著高于Ⅰ、Ⅱ期组（55.36±15.80,P<0.01）；TGF-βRⅡ表达水平(15.30±10.09)明显低于Ⅰ、Ⅱ期组（21.61±10.60, P<0.05）；Smad4蛋白表达水平在两组间差异无显著性（P＞0.05）。
4. 相关性分析：GC组TGF-β1与TGF-βRⅡ、TGF-β1与Smad4间存在显著直线负相关（r=-0.625，P＜0.01，r=-0.297，P＜0.05）；TGF-βRⅡ与Smad4间无明显直线相关性（P＞0.05）。NC组、IM组和Dys组各组内TGF-β1与TGF-βRⅡ、TGF-βRⅡ与Smad4、TGF-β1与Smad4间皆无明显直线相关性（P＞0.05）。各组间TGF-β1与TGF-βRⅡ间存在显著直线负相关（r=-0.820，P＜0.01），TGF-β1与Smad4以及TGF-βRⅡ与Smad4间无明显直线相关性（P＞0.05）。
结论：本研究结果表明：1. TGF-β1表达水平Dys组明显高于NC组，GC组显著高于NC组、IM组和Dys组，提示TGF-β1在胃癌前病变时已经异常升高，可能是胃癌形成过程中较早的一个生物学征象，检测TGF-β1可能有助于胃癌的早期
Objective：To investigate both the function of TGF-β1，TGF-βRⅡand Smad4 which belong to TGF-βsignal passway and the relationship among the three protein in the carcinogenesis and development of gastric cancer. We evaluated the expression of TGF-β1,TGF-βRⅡand Smad4 protein in gastric mucous of the patients with gastric cancer or precancerous leisions.
Methods：20 patients with intestinal metaplasia(IM),20 patients with dysplasia(Dys),46 patients with gastric cancer(GC) and 20 sex, age-matched health subjects were included in the present study. The diagnosis had been based on the gastric biopsies. According to the pathology report and surgery result, tumor were divided into such subgroups: well differentiation group(22 cases) and poorly differentiation group (24 cases);without regional lymph node invasion group(21 cases) and with regional lymph node invasion group(25 cases);without serosal invasion group (22 cases) and with serous invasion group(24 cases),without distant metastasis group(36 cases) and with distant metastasis
group(10 cases), stage (TNM)Ⅰ,Ⅱgroup(19 cases) and stage Ⅲ,Ⅳgroup(27 cases).All of the subjects had no other diseases. No GC patients had received chemotherapy or radiation therapy or other adjuvant therapy. 5 specimens(2 from antrum,2 from fundal and 1 from cornu gland region, big enough and fetched muscle)were obtained when they were performed by gastroscopy. All of the specimens were fixed with 10% Formalin and embedded with paraffin. They were cut into 5-μm thick sections. A serial section from each specimen was stained with hematoxylin and eosin (H & E) for histological evaluation. Immunohistochemical staining of the sections for TGF-β1,TGF-βRⅡ and Smad4 protein was performed by using image analysis system to get the result.
Results：1. TGF-β1 positive staining was observed in cytoplasm. Nomal epithelium positive cells was fewer and homogeneously stained,whereas in gastric cancerous tissue, more positive tumor cells were heterogeneously distributed and the color was deeper. TGF-βRⅡpositive staining was observed both in cytoplasm and cytomembrane. The positive cells were much more and the stain was also deeper in normal epithelium, while in gastric cancer tissue the positive cells were fewer and even no one is positive. In normal epithelium of the stomach, immunostaining of Smad4 was observed in cytoplasm and simultaneously in nuclei, while there was positive immunostaining for Smad4 only in the cytoplasm
in cancer cells and the stain was much weaker even lack of stain. 2.The expression level(positive areas%) of TGF-β1 in GC group was 64.62±14.71 which has a significant difference from NC group(18.97±10.86, P<0.01), IM group(24.42±13.45, P<0.01) and Dys group(33.60±14.61, P<0.01).There was no statistical significance between NC and IM group(p>0.05).The expression of TGF-β1 were much higher in Dys group than that in GC group(p>0.05).There was a significant difference among TGF-βRⅡexpression in GC group(17.91±10.66) and NC group(61.94±12.64, P<0.01),IM group(58.07±11.14, P<0.01) and Dys group(53.35±14.72, P<0.01). We didn't find statistical difference between NC and IM groups(p>0.05),IM and Dys groups(p>0.05). The expression of Smad4 protein in GC group was 23.57±14.31 which has a significant difference from NC group(70.33±12.13, p<0.01),IM group(67.93±13.93, p<0.01) and Dys group(68.82±13.22, p<0.01). We didn't find statistical difference between NC and IM gro ups(p>0.05), IM and Dys groups(p>0.05). 3.In GC group, the expression of TGF-β1 was significantly higher in poorly differentiation(71.29±10.05) than that in well differentiation(57.33±15.70,P<0.01). TGF-βRⅡand Smad4 protein staining in poorly differentiation group(14.09±9.63,16.64±12.81) was lower than that in well differentiation(22.08±10.35,P<0.01；30.22±12.20, P<0.01). With lymph node
invasion group, the expression of TGF-β1 was significantly higher(72.30±7.57) than that in without lymph node invasion group(55.47±16.02,P<0.01). TGF-βRⅡ was lower(14.82
方法：选择经胃镜活检病理组织学证实的肠上皮化生（IM）者20例、不典型增生（Dys）者20例及胃癌患者46例为试验组，其中胃癌患者全部手术。据病理和手术探查结果将46例胃癌按肿瘤组织学分化程度分为高中分化组（乳头状腺癌、管状腺癌，22例）和低分化组（低分化腺癌、印戒细胞癌，24例）；按有无区域淋巴结转移分为淋巴结转移组（25例）和无淋巴结转移组（21例）；按有无远处转移分为远处转移组（10例）和无远处转移组（36例）；按浸润深度分为累及浆膜组（24例）和未及浆膜组（22例）；按TNM分期（1988年国际抗癌联盟统一方案）分为TNMⅠ、Ⅱ期组（19例）和TNM Ⅲ、Ⅳ期组（27例）。另选20例胃镜观察及活检病理组织学基本正常者为对照组。所有入选者均排除心、脑、肝、肾、肠、胰腺等疾患。测试者均于行
胃镜检查时取胃黏膜标本5块（胃窦2块、胃体2块、胃角1块），标本足够大，深达黏膜肌。10％中性福尔马林固定4小时以上，石蜡包埋，连续切片，片厚5μm。常规HE染色，光镜下确定病理组织学类型。每例标本行免疫组化SABC法检测TGF-β1、TGF-βRⅡ、Smad4蛋白表达水平，病理图象分析系统处理切片染色结果。
结果：1.免疫组化染色显示：TGF-β1的阳性反应物位于胞浆内，在正常胃黏膜，TGF-β1阳性细胞较少，着色均匀，主要分布于黏膜表层；癌组织中，TGF-β1在胞浆内着色不均，呈棕褐色，颗粒状。TGF-βRⅡ的阳性反应物位于胞浆和（或）胞膜，在正常胃黏膜，TGF-βRⅡ呈弥漫或颗粒状染色；癌组织中TGF-βRⅡ表达较正常组织明显减弱甚至无表达。Smad4蛋白阳性反应物位于胞浆和（或）胞核，在正常胃黏膜，Smad4蛋白在胞浆和胞核中均有染色；胃癌细胞内，Smad4蛋白阳性染色较正常组织明显减弱甚至缺失，且阳性细胞胞核染色罕见。2. TGF-β1、TGF-βRⅡ和Smad4蛋白在各组中的表达水平变化：GC组TGF-β1蛋白表达水平（阳性面积％ 下同）为64.62±14.71，显著高于NC组（18.97±10.86，P<0.01）、IM组（24.42±13.45， P<0.01）和Dys组（33.60±14.61，P<0.01）；Dys组与NC间也有明显差异（P<0.05）；IM组与NC组间无明显差异（P＞0.05）。GC组TGF-βRⅡ表达水平为17.91
±10.66，显著低于NC组（61.94±12.64，P<0.01）、IM组（58.07±11.14，P<0.01）和Dys组（53.35±14.71，P<0.01）；IM组与NC组、Dys组与NC组间差异无显著性（P＞0.05，P＞0.05）。GC组Smad4蛋白表达水平为23.57±14.31，显著低于NC组（70.33±12.13，P<0.01）、IM组（67.93±13.93，P<0.01）和Dys组（68.82±13.22，P<0.01）；IM组与NC组、Dys组与NC组间差异无显著性（P＞0.05，P＞0.05）。3. GC组TGF-β1、TGF-βRⅡ和Smad4蛋白表达与临床病理的关系：胃癌组织学分化程度：低分化组中TGF-β1表达水平（71.29±10.05）显著高于高中分化组（57.33±15.70,P<0.01）；TGF-βRⅡ和Smad4蛋白表达水平(14.09±9.63,16.64±12.81)显著低于高中分化组（22.08±10.35, P<0.01；30.22±12.20, P<0.01）。区域淋巴结转移：有区域淋巴结转移组TGF-β1表达水平（72.30±7.57）显著高于无区域淋巴结转移组（55.47±16.02,P<0.01）； TGF-βRⅡ表达水平(14.82±10.78)显著低于无区域淋巴结转移组（21.59±9.50,P<0.01）；Smad4蛋白表达水平在两组间差异无显著性（P>0.05）。 远处转移：远处转移组Smad4蛋白表达水平（14.95±7.22）显著低于无远处转移组（27.08±12.32,P<0.01）；TGF-β1和TGF-βRⅡ表达水平在两组间差异无显著性（P>0.05）。浸润深度：累及浆膜组TGF-β1表达水平（68.73±12.55）明显高于未及浆膜组（60.13±15.84,P<0.05）；Smad4蛋
白表达水平（14.81±9.33）明显低于未及浆膜组（25.67±13.85,P<0.05）；TGF-βRⅡ表达水平在两组间差异无显著性（P＞0.05）。TNM分期：Ⅲ、Ⅳ期组TGF-β1表达水平（71.13±9.75）显著高于Ⅰ、Ⅱ期组（55.36±15.80,P<0.01）；TGF-βRⅡ表达水平(15.30±10.09)明显低于Ⅰ、Ⅱ期组（21.61±10.60, P<0.05）；Smad4蛋白表达水平在两组间差异无显著性（P＞0.05）。
4. 相关性分析：GC组TGF-β1与TGF-βRⅡ、TGF-β1与Smad4间存在显著直线负相关（r=-0.625，P＜0.01，r=-0.297，P＜0.05）；TGF-βRⅡ与Smad4间无明显直线相关性（P＞0.05）。NC组、IM组和Dys组各组内TGF-β1与TGF-βRⅡ、TGF-βRⅡ与Smad4、TGF-β1与Smad4间皆无明显直线相关性（P＞0.05）。各组间TGF-β1与TGF-βRⅡ间存在显著直线负相关（r=-0.820，P＜0.01），TGF-β1与Smad4以及TGF-βRⅡ与Smad4间无明显直线相关性（P＞0.05）。
结论：本研究结果表明：1. TGF-β1表达水平Dys组明显高于NC组，GC组显著高于NC组、IM组和Dys组，提示TGF-β1在胃癌前病变时已经异常升高，可能是胃癌形成过程中较早的一个生物学征象，检测TGF-β1可能有助于胃癌的早期
Objective：To investigate both the function of TGF-β1，TGF-βRⅡand Smad4 which belong to TGF-βsignal passway and the relationship among the three protein in the carcinogenesis and development of gastric cancer. We evaluated the expression of TGF-β1,TGF-βRⅡand Smad4 protein in gastric mucous of the patients with gastric cancer or precancerous leisions.
Methods：20 patients with intestinal metaplasia(IM),20 patients with dysplasia(Dys),46 patients with gastric cancer(GC) and 20 sex, age-matched health subjects were included in the present study. The diagnosis had been based on the gastric biopsies. According to the pathology report and surgery result, tumor were divided into such subgroups: well differentiation group(22 cases) and poorly differentiation group (24 cases);without regional lymph node invasion group(21 cases) and with regional lymph node invasion group(25 cases);without serosal invasion group (22 cases) and with serous invasion group(24 cases),without distant metastasis group(36 cases) and with distant metastasis
group(10 cases), stage (TNM)Ⅰ,Ⅱgroup(19 cases) and stage Ⅲ,Ⅳgroup(27 cases).All of the subjects had no other diseases. No GC patients had received chemotherapy or radiation therapy or other adjuvant therapy. 5 specimens(2 from antrum,2 from fundal and 1 from cornu gland region, big enough and fetched muscle)were obtained when they were performed by gastroscopy. All of the specimens were fixed with 10% Formalin and embedded with paraffin. They were cut into 5-μm thick sections. A serial section from each specimen was stained with hematoxylin and eosin (H & E) for histological evaluation. Immunohistochemical staining of the sections for TGF-β1,TGF-βRⅡ and Smad4 protein was performed by using image analysis system to get the result.
Results：1. TGF-β1 positive staining was observed in cytoplasm. Nomal epithelium positive cells was fewer and homogeneously stained,whereas in gastric cancerous tissue, more positive tumor cells were heterogeneously distributed and the color was deeper. TGF-βRⅡpositive staining was observed both in cytoplasm and cytomembrane. The positive cells were much more and the stain was also deeper in normal epithelium, while in gastric cancer tissue the positive cells were fewer and even no one is positive. In normal epithelium of the stomach, immunostaining of Smad4 was observed in cytoplasm and simultaneously in nuclei, while there was positive immunostaining for Smad4 only in the cytoplasm
in cancer cells and the stain was much weaker even lack of stain. 2.The expression level(positive areas%) of TGF-β1 in GC group was 64.62±14.71 which has a significant difference from NC group(18.97±10.86, P<0.01), IM group(24.42±13.45, P<0.01) and Dys group(33.60±14.61, P<0.01).There was no statistical significance between NC and IM group(p>0.05).The expression of TGF-β1 were much higher in Dys group than that in GC group(p>0.05).There was a significant difference among TGF-βRⅡexpression in GC group(17.91±10.66) and NC group(61.94±12.64, P<0.01),IM group(58.07±11.14, P<0.01) and Dys group(53.35±14.72, P<0.01). We didn't find statistical difference between NC and IM groups(p>0.05),IM and Dys groups(p>0.05). The expression of Smad4 protein in GC group was 23.57±14.31 which has a significant difference from NC group(70.33±12.13, p<0.01),IM group(67.93±13.93, p<0.01) and Dys group(68.82±13.22, p<0.01). We didn't find statistical difference between NC and IM gro ups(p>0.05), IM and Dys groups(p>0.05). 3.In GC group, the expression of TGF-β1 was significantly higher in poorly differentiation(71.29±10.05) than that in well differentiation(57.33±15.70,P<0.01). TGF-βRⅡand Smad4 protein staining in poorly differentiation group(14.09±9.63,16.64±12.81) was lower than that in well differentiation(22.08±10.35,P<0.01；30.22±12.20, P<0.01). With lymph node
invasion group, the expression of TGF-β1 was significantly higher(72.30±7.57) than that in without lymph node invasion group(55.47±16.02,P<0.01). TGF-βRⅡ was lower(14.82
引文
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4 出版社.1997,434~446
5 Alexandrow MG, Moses HL. Transforming growth factor β and cell cycle regulation. Cancer Res, 1995, 55(7): 1452~1457
6 Yoshiura K, Ota S, Terano A et al. Growth regulation of rabbit gastric epithelial cells and protooncogene expression. Digest Disease Sci, 1994, 39(7): 1454~1463
7 Yanagihara K, Tsumuraya M. Transforming growth factor β1 induces apoptosis cell death in cultured human gastric carcinomas cells. Cancer Res, 1992, 52(14): 4042~4045
8 Neaf M, Ishiwata T, Friess H et al. Differential localization of transforming growth factor beta isoform in human gastric mucosa and overexpressing in gastric cancer. Int J Cancer, 1997, 72(2): 131~137
9 许洪卫，王元和，谭益龙.组织和血清TGF-β1水平升高与胃癌侵袭性增强的相互关系.癌症,1999,18(2): 156~158
10 邓登豪,罗金燕, 朱海杭等.食管癌和异型增生中TGF-β1表达的意义.新消化病学杂志,1997,5(7):475
11 Ebert MP,Yu J,Miehlke S,et al.Expression of transforming growth factor β-1 in gastric cancer and in the gastric mucosa of first-degree relation of patients with gastric cancer. Br J Cancer, 2000, 82(11): 1795~1800
12 张川,江佛湖,戴强,等.转化生长因子-β在胃癌及癌旁组织中的表达及与细胞凋亡关系的实验研究.中华消化杂志, 2001, 21(9):569~570
13 Morisaki T, Katano M, Ikubo A etal. Immunosuppressive cytokines (IL-10, TGF-beta) gene expression in human gastric carcinoma tissues. J Surg Oncol, 1996, 63(4): 234~239
14 Maehara Y, Kakeji Y, Kabashima A et al. Role of transforming growth factor-β1 in invasion and metastasis in gastric carcinoma. J Clin Oncol, 1999, 17(2): 607~614
15 Choi YH, Choi KC, Park YE. Relationship of the transforming growth factor beta 1 to angiogenesis in gastric carcinoma. J Korean Med Sci, 1997, 12(5): 427~432
16 Saito H, Tsujitani S, Oka S, et al. The expression of transforming growth factor-beta 1 is significantly correlated with the expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric cancer. Cancer, 1999,86(8):1455~1462
17 Taipale J, Saharinen J, Keski Oja J, et al. Extracellular matrix-associated transforming growth factor-β: role in cancer cell growth and invasion. Adv Cancer Res, 1998, 75(1): 87~134
18 Niki M, Okajima K, Isozaaki H, et al. Measurement of the plasma transforming growth factor-beta 1 level in patients of gastric carcinoma compared with the serum IAP level and the lymphocyte subsets(CD3,CD4,CD8). Nippon Shokakibyo Gakkai Zasshi, 1996, 93(5):303~311
19 Wrana JL, Attisano L, Wieser R, et al. Mechanism of activation of the TGF-β receptor. Nature, 1994, 370(6488): 341~347
20 Ito M,Yasui W,Nakayama H,et al.Reduced levels of transforming growth factor-beta type Ⅰ receptor in human gastric carcinomas. Jpn J Cancer Res, 1992, 83(1): 86~92
21 Vostriukhina OA, Nikiforova IF, Shtam TA, et al. Damage to the transforming growth factor β type Ⅱ receptor gene and microsatelite instability in carcinoma cells of the gastrointestinal tract. Vopr Onkol, 1998, 44(6): 667~671
22 Takenosbita S, Mogi A, Osawa H et al. Absence of mutation in the analysis of coding sequences of the entire transforming growth factor-beta type Ⅱ receptor gene in sporadic humangastric cancer using genomic DNA and intron primers. Oncol Rep, 1998, 5(1):77~80
23 Shinmura K, Tani M, Isogaki J, et al. RER phenotype and its associated mutations in familial gastric cancer. Carcinogenesis, 1998, 19(2): 247~251
24 Grady WM, Myeroff LL, Swinler S, et al. Mutational inactivation of TGF-β receptor type Ⅱ in microsatellite stable colon cancers. Cancer Res, 1999, 59(4): 320~324
25 Maehara Y, Kakeji Y, Kabashima A, et al. Role of transforming growth factor beta 1 in invasion and metastasis in gastric carcinoma. J Clin Oncol, 1999, 17(2): 607~614
26 官国先,张祥福,杨发端.转化生长因子βⅡ型受体在胃癌组织中表达水平与侵袭、转移的相关性研究.肿瘤, 1999, 19(4):216~219
27 Park D 2nd, Son HJ, Song SY, et al. Role of TGF-beta 1 and TGF-beta type II receptor in gastric cancer. Korean J Intern Med, 2002, 17(3): 160~166
28 萧树东.消化病学新理论与新技术,上海科技教育出版社. 1999, 97~106
29 Toscila M, Skinner HG, Rosty C, et al. The Smad4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res, 2001, 7(12): 4115~4121
30 Xie W, Mertens JC, Reiss DJ, et al. Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. Cancer Res, 2002, 62(2):497~505
31 Hahn SA, Schutte M, Hoque ATMS, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, 1996, 271(5247): 350~353
32 Xu X, Brodie SG, Yang X, et al. Haploid loss of the suppressor Smad4/DPC4 initiates gastric polyposis and cancer in mice. Oncogene, 2000,19(15):1868~1874
33 刘华,许春进,陈玉龙等.转化生长因子β1和Smad4在胃癌中的表达.中华消化杂志,2002,22(12):730~732
34 Xiangming C, Natsugoe S, Takao S, et al. Preserved Smad4 expression in the transforming growth factor β signaling pathway is a favorable prognostic factor in patients with advanced gastric cancer. Clin Cancer Res, 2001, 7(2):277~282
35 Schwarte-Waldhoff I, Volpert OV, Bouck, NP, et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci USA, 2000, 97(17):9624~9629
36 李国庆,丰义宽,周海波等.食管癌、胃癌和结直肠癌DPC4基因的失活与突变. 中华消化杂志, 2002, 22(4): 253~254
37 Powell SM, Harper JC, Hamilton SR, et al. Inactivation of Smad4 in gastric carcinomas. Cancer Res, 1997, 57(19): 4221~4224
38 Nishiznka S, Tamura G, Maesawa C, et al. Analysis of the DPC4 gene in gastric cancer. Jpn J Cancer Res, 1997, 88(4): 335~339
39 Tamura G, Sakata K, Nishiznka S, et al. Auelotype of adenoma and differentialed adenocarcinoma of the stomach. J Pathol, 1996, 180(4):371~377
40 Uchino S, Tsuda H, Noguchi M, et al. Frequent loss of heterozygosity at the DCC locus in gastric cancer. Cancer Res, 1992, 152(11):3099~3102
Xu J,Attisano L.Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor
41 beta signaling by targeting Smads to the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA, 2000, 97(9): 4820~4825
42 Saha D, Datta PK, Beauchamp RD et al. Oncogenic ras represses transforming growth factor-beta/Smad signaling by degrading tumor suppressor Smad4. J Biol Chem, 2001, 276(31): 29531~29537
43 Fink SP, Swinler SE, Lutterbaugh JD et al. transforming growth factor beta induced growth inhibition in a Smad4 mutant colon adenoma cell line. Cancer Res, 2001, 61(1): 256~260
2 Tanaka S, Mori M, Mafune K, et al. A donimanr negarive mutation of transforming growth factor-beta receptor type Ⅱ gene in microsatellite stable oesophageal carcinoma. Br J Cancer, 2000,82(9): 1557~1560
3 李其云,牛凤霞,李文雁等.胃癌细胞凋亡与增殖的观察.临床与实验病理学杂志,2001,17(3):205~208
陈元方.胃肠肽类激素基础与临床.北京医科大学中国协和医科大学联合
4 出版社.1997,434~446
5 Alexandrow MG, Moses HL. Transforming growth factor β and cell cycle regulation. Cancer Res, 1995, 55(7): 1452~1457
6 Yoshiura K, Ota S, Terano A et al. Growth regulation of rabbit gastric epithelial cells and protooncogene expression. Digest Disease Sci, 1994, 39(7): 1454~1463
7 Yanagihara K, Tsumuraya M. Transforming growth factor β1 induces apoptosis cell death in cultured human gastric carcinomas cells. Cancer Res, 1992, 52(14): 4042~4045
8 Neaf M, Ishiwata T, Friess H et al. Differential localization of transforming growth factor beta isoform in human gastric mucosa and overexpressing in gastric cancer. Int J Cancer, 1997, 72(2): 131~137
9 许洪卫，王元和，谭益龙.组织和血清TGF-β1水平升高与胃癌侵袭性增强的相互关系.癌症,1999,18(2): 156~158
10 邓登豪,罗金燕, 朱海杭等.食管癌和异型增生中TGF-β1表达的意义.新消化病学杂志,1997,5(7):475
11 Ebert MP,Yu J,Miehlke S,et al.Expression of transforming growth factor β-1 in gastric cancer and in the gastric mucosa of first-degree relation of patients with gastric cancer. Br J Cancer, 2000, 82(11): 1795~1800
12 张川,江佛湖,戴强,等.转化生长因子-β在胃癌及癌旁组织中的表达及与细胞凋亡关系的实验研究.中华消化杂志, 2001, 21(9):569~570
13 Morisaki T, Katano M, Ikubo A etal. Immunosuppressive cytokines (IL-10, TGF-beta) gene expression in human gastric carcinoma tissues. J Surg Oncol, 1996, 63(4): 234~239
14 Maehara Y, Kakeji Y, Kabashima A et al. Role of transforming growth factor-β1 in invasion and metastasis in gastric carcinoma. J Clin Oncol, 1999, 17(2): 607~614
15 Choi YH, Choi KC, Park YE. Relationship of the transforming growth factor beta 1 to angiogenesis in gastric carcinoma. J Korean Med Sci, 1997, 12(5): 427~432
16 Saito H, Tsujitani S, Oka S, et al. The expression of transforming growth factor-beta 1 is significantly correlated with the expression of vascular endothelial growth factor and poor prognosis of patients with advanced gastric cancer. Cancer, 1999,86(8):1455~1462
17 Taipale J, Saharinen J, Keski Oja J, et al. Extracellular matrix-associated transforming growth factor-β: role in cancer cell growth and invasion. Adv Cancer Res, 1998, 75(1): 87~134
18 Niki M, Okajima K, Isozaaki H, et al. Measurement of the plasma transforming growth factor-beta 1 level in patients of gastric carcinoma compared with the serum IAP level and the lymphocyte subsets(CD3,CD4,CD8). Nippon Shokakibyo Gakkai Zasshi, 1996, 93(5):303~311
19 Wrana JL, Attisano L, Wieser R, et al. Mechanism of activation of the TGF-β receptor. Nature, 1994, 370(6488): 341~347
20 Ito M,Yasui W,Nakayama H,et al.Reduced levels of transforming growth factor-beta type Ⅰ receptor in human gastric carcinomas. Jpn J Cancer Res, 1992, 83(1): 86~92
21 Vostriukhina OA, Nikiforova IF, Shtam TA, et al. Damage to the transforming growth factor β type Ⅱ receptor gene and microsatelite instability in carcinoma cells of the gastrointestinal tract. Vopr Onkol, 1998, 44(6): 667~671
22 Takenosbita S, Mogi A, Osawa H et al. Absence of mutation in the analysis of coding sequences of the entire transforming growth factor-beta type Ⅱ receptor gene in sporadic humangastric cancer using genomic DNA and intron primers. Oncol Rep, 1998, 5(1):77~80
23 Shinmura K, Tani M, Isogaki J, et al. RER phenotype and its associated mutations in familial gastric cancer. Carcinogenesis, 1998, 19(2): 247~251
24 Grady WM, Myeroff LL, Swinler S, et al. Mutational inactivation of TGF-β receptor type Ⅱ in microsatellite stable colon cancers. Cancer Res, 1999, 59(4): 320~324
25 Maehara Y, Kakeji Y, Kabashima A, et al. Role of transforming growth factor beta 1 in invasion and metastasis in gastric carcinoma. J Clin Oncol, 1999, 17(2): 607~614
26 官国先,张祥福,杨发端.转化生长因子βⅡ型受体在胃癌组织中表达水平与侵袭、转移的相关性研究.肿瘤, 1999, 19(4):216~219
27 Park D 2nd, Son HJ, Song SY, et al. Role of TGF-beta 1 and TGF-beta type II receptor in gastric cancer. Korean J Intern Med, 2002, 17(3): 160~166
28 萧树东.消化病学新理论与新技术,上海科技教育出版社. 1999, 97~106
29 Toscila M, Skinner HG, Rosty C, et al. The Smad4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res, 2001, 7(12): 4115~4121
30 Xie W, Mertens JC, Reiss DJ, et al. Alterations of Smad signaling in human breast carcinoma are associated with poor outcome: a tissue microarray study. Cancer Res, 2002, 62(2):497~505
31 Hahn SA, Schutte M, Hoque ATMS, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science, 1996, 271(5247): 350~353
32 Xu X, Brodie SG, Yang X, et al. Haploid loss of the suppressor Smad4/DPC4 initiates gastric polyposis and cancer in mice. Oncogene, 2000,19(15):1868~1874
33 刘华,许春进,陈玉龙等.转化生长因子β1和Smad4在胃癌中的表达.中华消化杂志,2002,22(12):730~732
34 Xiangming C, Natsugoe S, Takao S, et al. Preserved Smad4 expression in the transforming growth factor β signaling pathway is a favorable prognostic factor in patients with advanced gastric cancer. Clin Cancer Res, 2001, 7(2):277~282
35 Schwarte-Waldhoff I, Volpert OV, Bouck, NP, et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci USA, 2000, 97(17):9624~9629
36 李国庆,丰义宽,周海波等.食管癌、胃癌和结直肠癌DPC4基因的失活与突变. 中华消化杂志, 2002, 22(4): 253~254
37 Powell SM, Harper JC, Hamilton SR, et al. Inactivation of Smad4 in gastric carcinomas. Cancer Res, 1997, 57(19): 4221~4224
38 Nishiznka S, Tamura G, Maesawa C, et al. Analysis of the DPC4 gene in gastric cancer. Jpn J Cancer Res, 1997, 88(4): 335~339
39 Tamura G, Sakata K, Nishiznka S, et al. Auelotype of adenoma and differentialed adenocarcinoma of the stomach. J Pathol, 1996, 180(4):371~377
40 Uchino S, Tsuda H, Noguchi M, et al. Frequent loss of heterozygosity at the DCC locus in gastric cancer. Cancer Res, 1992, 152(11):3099~3102
Xu J,Attisano L.Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor
41 beta signaling by targeting Smads to the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA, 2000, 97(9): 4820~4825
42 Saha D, Datta PK, Beauchamp RD et al. Oncogenic ras represses transforming growth factor-beta/Smad signaling by degrading tumor suppressor Smad4. J Biol Chem, 2001, 276(31): 29531~29537
43 Fink SP, Swinler SE, Lutterbaugh JD et al. transforming growth factor beta induced growth inhibition in a Smad4 mutant colon adenoma cell line. Cancer Res, 2001, 61(1): 256~260