Her-2，Slug和E-cadherin与胃癌组织学分型和预后的关系
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摘要
胃癌是世界上第四位常见恶性肿瘤,癌症第二大死因。国内临床调查显示胃癌被发现时90%以上处于进展期,即使施行了胃癌根治术,5年生存率仍然低。传统的组织病理学诊断是肿瘤诊断和治疗的基础,但即使组织学类型相同的肿瘤如采取相同的治疗方案,预后并不一致。因此在组织学分型基础上寻找能够有效评估预后、警示转移复发的临床、病理指标和分子标志物及其相应的靶向治疗药物成为胃癌研究工作者不懈探索的目标。
Ras/Raf/MAPK和PI3K/Akt信号通路与肿瘤关系密切,受体酪氨酸激酶(RTKs)活化后可以激活这两条通路。表皮生长因子受体(Her-2)为RTKs家族一员,活化后可激活Ras/Raf/MAPK和PI3K/Akt通路,引发一系列细胞生物学改变。乳腺癌中发现Her-2与复发和预后有关,Her-2阳性的乳腺癌易复发、预后差。针对Her-2的靶向治疗药物曲妥珠单抗对Her-2阳性的乳腺癌病例的治疗已取得明确疗效。有资料显示Her-2在胃癌中也发挥重要作用,而且曲妥珠单抗已经进入胃癌治疗Ⅲ期临床试验,取得疗效,但Her-2在胃癌的表达与预后报道不尽一致,亟需有大样本的临床病理和预后数据。
另一方面,Ras/Raf/MAPK信号通路通过下游的信号分子进入细胞核内作用于上皮间质转化(Epithelial Mesenchymal Transition, EMT)诱导转录因子Snail家族,使其下游基因E-cd表达下调。Slug/Snai2是该家族成员之一。北京肿瘤防治研究所前期的基因表达谱信息分析显示Slug在低分化胃癌中高表达,在高分化胃癌中低表达,而其下游的E-钙黏蛋白(E-cadherin,E-cd)的表达刚好与之相反,提示Slug和E-cd可能与胃癌的分化有关,有可能是与胃癌分化、预后相关的分子标志物。
基于此,我们首先对486例胃癌病例进行WHO和Lauren组织学分型与预后再评估,结果显示发病年龄、有无脉管浸润、淋巴结转移情况(包括pN分期和N ratio分级)及pTNM分期是胃癌的独立预后因素,WHO和Lauren分型并非是胃癌的独立预后因子。其次我们分别用免疫组织化学和荧光免疫原位杂交技术检测了486例胃癌Her-2的过表达和基因扩增情况,并分析Her-2状态与胃癌临床病理的联系及预后意义,结果显示Her-2阳性率为10.93%,其阳性与WHO组织学分型(P=0.011)、分级(P=0.000)和Lauren分型(P=0.024)有关,乳头状腺癌和管状腺癌、组织学分级低和肠型胃癌病例Her-2阳性率更高,但Her-2状态与胃癌总体生存率无关(P=0.709),但在印戒细胞癌或弥漫型胃癌,有迹象表明Her-2阳性组较阴性组预后更差,但因HER2阳性例数较少,两组差异均无统计学意义。
进一步,我们探讨了Slug和E-cd的表达及其与预后的关系。检测了Slug和E-cd在胃癌细胞系中mRNA和蛋白水平的表达并对两者的相关性进行分析,对高致瘤性的胃癌细胞株SGC7901进行Slug的化学干扰,证实其与E-cd的关系。然后利用组织芯片和免疫组织化学技术,检测Slug和E-cd在486例胃癌组织中的表达,分析其与胃癌浸润、转移的关系,并结合临床病理学特征和预后进行综合评价。细胞系实验结果显示在mRNA和蛋白水平,Slug在致瘤性高的胃癌细胞系BGC823、MGC803和SGC7901中均高表达,在致瘤性弱的胃癌细胞系AGS和N87中基本不表达。E-cd的表达趋势则与之相反,在致瘤性高的3株胃癌细胞系低表达,而在致瘤性弱的细胞系AGS和N87高表达。对高表达Slug的胃癌细胞系SGC7901进行化学干扰后,E-cdmRNA表达上调1.9～2.9倍。胃癌组织的检测结果显示Slug与E-cd的表达呈正相关,Slug的蛋白表达与患者年龄、肿瘤发生部位、浸润深度、WHO组织学分型、分级、Lauren分型、淋巴结转移和pTNM分期有关。生存分析显示在胃周淋巴结总数≥15个的病例组,Slug与pN、pTNM分期都是胃癌的独立预后因素,提示Slug可能是与胃癌预后相关的标志物。E-cd的蛋白表达水平与性别、年龄、肿瘤部位、WHO组织学分型、分级以及Lauren分型有关,但与肿瘤大小、浸润深度、脉管癌栓、淋巴结转移和pTNM分期无关。单因素及多因素生存分析都显示E-cd与胃癌预后无关,提示E-cd可能为一分化标志物,与胃癌预后无关。
以上结果表明,WHO和Lauren组织学分型仍然是深入研究胃癌的基础；Her-2状态没有明确的预后价值；Slug与pN、pTNM分期都是胃癌预后独立因素；E-cd则更倾向于分化标志物,而与胃癌预后无关。
Gastric carcinoma(GC) still remains the fourth most common cancer worldwide and is the second cause of cancer related death. Clinically more than 90% of GC cases are in advanced stage. Even though radical gastrectomy is performed, the prognosis is still dismal with a low 5-year survival rate. Histopathological diagnosis and classification is the foundation of subsequent treatment. However, prognosis differs even in cases with identical histological type and uniform therapy. Great efforts were made to correlate the clinicopathological parameters with prognosis and molecular markers have been searching in recent years to predict the prognosis.
Ras/Raf/MAPK and PI3K/Akt signaling pathways play important roles in GC. Receptor tyrosine kinases (RTKs) can activate these two pathways. Her-2, as a member of epidermal growth factor receptors, belongs to RTKs which regulate many basic cellular processes through Ras/Raf/MAPK and PI3K/Akt. In the case of breast carcinoma, overexpression of Her-2 protein or amplification of Her-2 gene was associated with recurrence and poor prognosis. A new therapeutic agent trastuzumab as a monoclonal antibody to Her-2 has been shown to be effective in Her-2 positive breast carcinoma patients. Data also showed that Her-2 played an important role in GC development. Recently, a global clinical study was conducted to determine response to trastuzumab therapy in Her-2 positive GC patients. However the frequency of Her-2 positivity varied from different studies and its clinical significance in gastric cancer is yet not clear. A large-sample clinicopathological observation and analysis concerning Her-2 status is still needed.
On the other hand, Ras/Raf/MAPK pathway may finally affect the transcription factor-Snail family which induce epithelial mesenchymal transition(EMT) by downregulating E-cd. Slug/Snai2 is a member of Snail family. According to the gene expression profiling of Beijing Institute of Cancer Research, transcription factor Slug mRNA level was increased in poorly differentiated GC, but decreased in well differentiated one. E-cd mRNA expression level was the reverse. So we hypothesized that Slug and E-cd may be correlated with differentiation and prognosis in GC.
Thus firstly we re-evaluated prognostic significance of WHO and Lauren classification by reviewing HE sections of 486 gastric cancer patients who underwent curative gastrectomy from January 2001 to December 2004 in PLA General Hospital. Statistical analysis demonstrated that age, lymphatic/vascular invasion, lymph node metastasis (including pN stage and N ratio grade) and pTNM stage were independent prognostic factors. Although WHO and Lauren classification had significant influence on overall survival in univariate analysis, they lost their independent value in multivariate analysis.
Subsequently, to clarify the potential clinical relevance of Her-2 status in gastric cancer, we evaluated Her-2 status in 486 cases of GC by applying immunohistochemistry(IHC) and Fluorescence in situ hybridiza-tion(FISH), then correlated its positivity with clinicopathological parameters and follow-up data. Her-2 positivity was found in 10.93% of GC cases. Her-2 positive status were common in cases with papillary and glandular adenocarcinomas according to WHO classification (P=0.011), in cases with a well or moderately differentiated GC by WHO histological grade (P=0.000) and in cases of intestinal type by Lauren classification (P=0.024). Survival analysis revealed that the overall survival between Her-2 positive and negative cases showed no significant difference (P=0.709). Yet in signet ring cell carcinoma or diffuse GC, the 5-year survival rate of Her-2 positive cases was 0%, indicating worse prognosis. However, the difference was not statistically significant probably due to the fewer Her-2 positive cases.
In the third part of the study, we explored the significance of Slug and E-cd in GC cell lines as well as in 486 GC cases. Initially we examined their expression in 6 GC cell lines at mRNA and protein level respectively, analyzed the role of Slug in relation with E-cd through silencing of Slug by short hairpin RNA. Then we investigated Slug and E-cd expression using tissue array and IHC method. Meanwhile, we analyzed the association of Slug and E-cd expression with clinicopathological parameters and prognosis. An increased Slug expression was observed in BGC823、MGC803 and SGC7901 GC cell lines which had greater capacity of tumorgenesis, while Slug expression level was low in AGS and N87 at both mRNA and protein level. Inversely, E-cd expression was low in BGC823、MGC803 and SGC7901 GC cell lines, while it was increased in AGS and N87 GC cell lines at both mRNA and protein level. In MKN45 GC cell line, a sequence of 12 bases was found missing by gene sequencing. Transient Slug silencing in SGC7901 cell line induced an increase in E-cd mRNA level up to 2.9-fold. Positive expression of Slug and E-cd was observed in 56.2% and 69.1% GC cases, respectively, which was positively correlated. The expression of Slug correlated with age, tumor location, depth of invasion, WHO classification, WHO histological grade, Lauren classification, lymph node metastasis status and pTNM stage. Though univariate analysis revealed Slug expression was unrelated to survival, multivariate analysis indicated that Slug expression was an independent prognostic factor in addition to pN, pTNM stage. The expression of E-cd correlated with gender, age, tumor location, WHO classification, WHO histological grade and Lauren classification, but unrelated with tumor size, depth of invasion, lymphatic/vascular invasion, lymph node metastasis or pTNM stage. Neither univariate nor multivariate analysis showed E-cd expression had a significant impact on patient's overall survival.
In conclusion, precise WHO and Lauren classification remains the baseline study of GC. Her-2 status is not related to the prognosis.Slug expression is an independent prognostic factor in addition to pN, pTNM stage. E-cd tends to be a differentiation marker rather than a prognostic one.
Ras/Raf/MAPK和PI3K/Akt信号通路与肿瘤关系密切,受体酪氨酸激酶(RTKs)活化后可以激活这两条通路。表皮生长因子受体(Her-2)为RTKs家族一员,活化后可激活Ras/Raf/MAPK和PI3K/Akt通路,引发一系列细胞生物学改变。乳腺癌中发现Her-2与复发和预后有关,Her-2阳性的乳腺癌易复发、预后差。针对Her-2的靶向治疗药物曲妥珠单抗对Her-2阳性的乳腺癌病例的治疗已取得明确疗效。有资料显示Her-2在胃癌中也发挥重要作用,而且曲妥珠单抗已经进入胃癌治疗Ⅲ期临床试验,取得疗效,但Her-2在胃癌的表达与预后报道不尽一致,亟需有大样本的临床病理和预后数据。
另一方面,Ras/Raf/MAPK信号通路通过下游的信号分子进入细胞核内作用于上皮间质转化(Epithelial Mesenchymal Transition, EMT)诱导转录因子Snail家族,使其下游基因E-cd表达下调。Slug/Snai2是该家族成员之一。北京肿瘤防治研究所前期的基因表达谱信息分析显示Slug在低分化胃癌中高表达,在高分化胃癌中低表达,而其下游的E-钙黏蛋白(E-cadherin,E-cd)的表达刚好与之相反,提示Slug和E-cd可能与胃癌的分化有关,有可能是与胃癌分化、预后相关的分子标志物。
基于此,我们首先对486例胃癌病例进行WHO和Lauren组织学分型与预后再评估,结果显示发病年龄、有无脉管浸润、淋巴结转移情况(包括pN分期和N ratio分级)及pTNM分期是胃癌的独立预后因素,WHO和Lauren分型并非是胃癌的独立预后因子。其次我们分别用免疫组织化学和荧光免疫原位杂交技术检测了486例胃癌Her-2的过表达和基因扩增情况,并分析Her-2状态与胃癌临床病理的联系及预后意义,结果显示Her-2阳性率为10.93%,其阳性与WHO组织学分型(P=0.011)、分级(P=0.000)和Lauren分型(P=0.024)有关,乳头状腺癌和管状腺癌、组织学分级低和肠型胃癌病例Her-2阳性率更高,但Her-2状态与胃癌总体生存率无关(P=0.709),但在印戒细胞癌或弥漫型胃癌,有迹象表明Her-2阳性组较阴性组预后更差,但因HER2阳性例数较少,两组差异均无统计学意义。
进一步,我们探讨了Slug和E-cd的表达及其与预后的关系。检测了Slug和E-cd在胃癌细胞系中mRNA和蛋白水平的表达并对两者的相关性进行分析,对高致瘤性的胃癌细胞株SGC7901进行Slug的化学干扰,证实其与E-cd的关系。然后利用组织芯片和免疫组织化学技术,检测Slug和E-cd在486例胃癌组织中的表达,分析其与胃癌浸润、转移的关系,并结合临床病理学特征和预后进行综合评价。细胞系实验结果显示在mRNA和蛋白水平,Slug在致瘤性高的胃癌细胞系BGC823、MGC803和SGC7901中均高表达,在致瘤性弱的胃癌细胞系AGS和N87中基本不表达。E-cd的表达趋势则与之相反,在致瘤性高的3株胃癌细胞系低表达,而在致瘤性弱的细胞系AGS和N87高表达。对高表达Slug的胃癌细胞系SGC7901进行化学干扰后,E-cdmRNA表达上调1.9～2.9倍。胃癌组织的检测结果显示Slug与E-cd的表达呈正相关,Slug的蛋白表达与患者年龄、肿瘤发生部位、浸润深度、WHO组织学分型、分级、Lauren分型、淋巴结转移和pTNM分期有关。生存分析显示在胃周淋巴结总数≥15个的病例组,Slug与pN、pTNM分期都是胃癌的独立预后因素,提示Slug可能是与胃癌预后相关的标志物。E-cd的蛋白表达水平与性别、年龄、肿瘤部位、WHO组织学分型、分级以及Lauren分型有关,但与肿瘤大小、浸润深度、脉管癌栓、淋巴结转移和pTNM分期无关。单因素及多因素生存分析都显示E-cd与胃癌预后无关,提示E-cd可能为一分化标志物,与胃癌预后无关。
以上结果表明,WHO和Lauren组织学分型仍然是深入研究胃癌的基础；Her-2状态没有明确的预后价值；Slug与pN、pTNM分期都是胃癌预后独立因素；E-cd则更倾向于分化标志物,而与胃癌预后无关。
Gastric carcinoma(GC) still remains the fourth most common cancer worldwide and is the second cause of cancer related death. Clinically more than 90% of GC cases are in advanced stage. Even though radical gastrectomy is performed, the prognosis is still dismal with a low 5-year survival rate. Histopathological diagnosis and classification is the foundation of subsequent treatment. However, prognosis differs even in cases with identical histological type and uniform therapy. Great efforts were made to correlate the clinicopathological parameters with prognosis and molecular markers have been searching in recent years to predict the prognosis.
Ras/Raf/MAPK and PI3K/Akt signaling pathways play important roles in GC. Receptor tyrosine kinases (RTKs) can activate these two pathways. Her-2, as a member of epidermal growth factor receptors, belongs to RTKs which regulate many basic cellular processes through Ras/Raf/MAPK and PI3K/Akt. In the case of breast carcinoma, overexpression of Her-2 protein or amplification of Her-2 gene was associated with recurrence and poor prognosis. A new therapeutic agent trastuzumab as a monoclonal antibody to Her-2 has been shown to be effective in Her-2 positive breast carcinoma patients. Data also showed that Her-2 played an important role in GC development. Recently, a global clinical study was conducted to determine response to trastuzumab therapy in Her-2 positive GC patients. However the frequency of Her-2 positivity varied from different studies and its clinical significance in gastric cancer is yet not clear. A large-sample clinicopathological observation and analysis concerning Her-2 status is still needed.
On the other hand, Ras/Raf/MAPK pathway may finally affect the transcription factor-Snail family which induce epithelial mesenchymal transition(EMT) by downregulating E-cd. Slug/Snai2 is a member of Snail family. According to the gene expression profiling of Beijing Institute of Cancer Research, transcription factor Slug mRNA level was increased in poorly differentiated GC, but decreased in well differentiated one. E-cd mRNA expression level was the reverse. So we hypothesized that Slug and E-cd may be correlated with differentiation and prognosis in GC.
Thus firstly we re-evaluated prognostic significance of WHO and Lauren classification by reviewing HE sections of 486 gastric cancer patients who underwent curative gastrectomy from January 2001 to December 2004 in PLA General Hospital. Statistical analysis demonstrated that age, lymphatic/vascular invasion, lymph node metastasis (including pN stage and N ratio grade) and pTNM stage were independent prognostic factors. Although WHO and Lauren classification had significant influence on overall survival in univariate analysis, they lost their independent value in multivariate analysis.
Subsequently, to clarify the potential clinical relevance of Her-2 status in gastric cancer, we evaluated Her-2 status in 486 cases of GC by applying immunohistochemistry(IHC) and Fluorescence in situ hybridiza-tion(FISH), then correlated its positivity with clinicopathological parameters and follow-up data. Her-2 positivity was found in 10.93% of GC cases. Her-2 positive status were common in cases with papillary and glandular adenocarcinomas according to WHO classification (P=0.011), in cases with a well or moderately differentiated GC by WHO histological grade (P=0.000) and in cases of intestinal type by Lauren classification (P=0.024). Survival analysis revealed that the overall survival between Her-2 positive and negative cases showed no significant difference (P=0.709). Yet in signet ring cell carcinoma or diffuse GC, the 5-year survival rate of Her-2 positive cases was 0%, indicating worse prognosis. However, the difference was not statistically significant probably due to the fewer Her-2 positive cases.
In the third part of the study, we explored the significance of Slug and E-cd in GC cell lines as well as in 486 GC cases. Initially we examined their expression in 6 GC cell lines at mRNA and protein level respectively, analyzed the role of Slug in relation with E-cd through silencing of Slug by short hairpin RNA. Then we investigated Slug and E-cd expression using tissue array and IHC method. Meanwhile, we analyzed the association of Slug and E-cd expression with clinicopathological parameters and prognosis. An increased Slug expression was observed in BGC823、MGC803 and SGC7901 GC cell lines which had greater capacity of tumorgenesis, while Slug expression level was low in AGS and N87 at both mRNA and protein level. Inversely, E-cd expression was low in BGC823、MGC803 and SGC7901 GC cell lines, while it was increased in AGS and N87 GC cell lines at both mRNA and protein level. In MKN45 GC cell line, a sequence of 12 bases was found missing by gene sequencing. Transient Slug silencing in SGC7901 cell line induced an increase in E-cd mRNA level up to 2.9-fold. Positive expression of Slug and E-cd was observed in 56.2% and 69.1% GC cases, respectively, which was positively correlated. The expression of Slug correlated with age, tumor location, depth of invasion, WHO classification, WHO histological grade, Lauren classification, lymph node metastasis status and pTNM stage. Though univariate analysis revealed Slug expression was unrelated to survival, multivariate analysis indicated that Slug expression was an independent prognostic factor in addition to pN, pTNM stage. The expression of E-cd correlated with gender, age, tumor location, WHO classification, WHO histological grade and Lauren classification, but unrelated with tumor size, depth of invasion, lymphatic/vascular invasion, lymph node metastasis or pTNM stage. Neither univariate nor multivariate analysis showed E-cd expression had a significant impact on patient's overall survival.
In conclusion, precise WHO and Lauren classification remains the baseline study of GC. Her-2 status is not related to the prognosis.Slug expression is an independent prognostic factor in addition to pN, pTNM stage. E-cd tends to be a differentiation marker rather than a prognostic one.
引文
参考文献
1. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006,12(3):354-362.
2. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002. CA Cancer J Clin.2005,55(2):74-108.
3. Wang XQ, Terry PD, Yan H. Review of salt consumption and stomach cancer risk:epidemiological and biological evidence. World J Gastroenterol.2009, 15(18):2204-2213.
4.孙秀娣,牧人,周有尚,等.中国胃癌死亡率20年变化情况分析及其发展趋势预测.中华肿瘤杂志.2004,26(1)：4-9.
5. Lauren, P. The two histological main types of gastric carcinoma:diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand.1965,64: 31-49.
6. Owen DA. The Stomach. In:Stenberg SS, Antonioli D, Carter D, Mills SE, Oberman HA, eds. Diagnostic Surgical Pathology.3rd ed. New York: Lippincott Williams and Wilkins,1999:1311-49.
7. Fenoglio-Preiser, Noffsinder AE, Stemmermann GN, et al. Gastroentestinal Pathology, an Aatlas and Text.2nd. Philadelphia-New York: Lippincott-Raven,1998.
8. Ming SC. Gastric carcinoma. A pathobiological classification. Cancer.1977, 39(6):2475-85.
9. Goseki N, Takizawa T, Koike M. Differences in the mode of the extension of gatric cancer classified by histological type:new histologic classification of gastric carcinoma. Gut.1992,33(5):606-612.
10. Cimerman M, Repse S, Jelenc F, et al. Comparison of Lauren's, Ming's and WHO histological classifications of gastric cancer as a prognostic factor for operated patients. Int Surg.1994,79(1):27-32.
11. Luebke T, Baldus SE, Grass G, et al. Histological grading in gastric cancer by Ming classification:correlation with histopathological subtypes, metastasis, and prognosis. World J Surg.2005,29(1l):1422-1427.
12. Lee WS, Song HS, Kim IH, et al. Prognostic significance of Lauren classification in curatively resected gastric cancer. Proc Am Soc Clin Oncol. 22:2003(abstr 1453).
13. Calli Demirkan N, Tuncyurek M, Ugur Ertan E, et al. Correlation of histological classifications of gastric carcinomas with location and prognosis. Gastroenterol Clin Biol.2002,26(6-7):610-5.
14. Liang B, Wang S, Zhu X Q et al. Increased expression of MAPKs and its upstream regulating signal in human gastric cancer. World J Gastroenterol. 2005,11(5):623-8.
15. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states:acquisition of malignant and stem cell traits. cancer.2009,9(4): 265-273.
16. Ono M, Kuwano M. Molecularmechanisms of epidermal growth factor receptor(EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res.2006,12(24):7242-7251.
17. Goueli BS, JanknechtR. Upregulation of the catalytic telomerase subunit by the transcription factor ER81and oncogenic HER2/Neu, Ras, or Raf. Mol Cell Biol.2004,24(1):25-35.
18. Dowdy SC, Mariani A, Janknecht R. HER2/neu and TAK1-mediated up-regulation of the transforming growth factor-beta inhibitor Smad7 via the ETS protein ER81. J Biol Chem.2003,278(45):44377-44384.
19. Finkenzeller G, Weindel K, Zimmermann W, et al. Activated Neu/ErbB-2 induces expression of the vascular endothelial growth factor gene by functional activation of the transcription factor Sp1. Angiogenesis. 2004,7(1):59-68.
20. Tanner M, Hollmen M, Junttila TT, et al. Amplification of HER-2 in gastric carcinoma:association with Topoisomerase Ⅱ alpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005,16(2):273-8.
21. Rebischung C, Barnoud R, Stefani L, et al. The effectiveness of trastuzumab (herceptin) combined with chemotherapy for gastric carcinoma with overexpression of the c-erbB-2 protein. Gastric Cancer.2005,8(4):249-252.
22. Boyer B, Valles AM, and Edme N. Induction and regulation of epithelial-mesenchymal transitions. Biochem Pharmacol.2000,60(8):1091-1099.
23. Thiery JP. Epithelial-mesenchymal transition in tumor progression. Nature Rev Cancer.2002,2:442-454.
1.赵刚,邱江锋,吴志勇.603例胃癌根治术的预后因素分析.中国癌症杂志.2007,17(7)：556-559.
2.李景武,梁寒,王晓娜.814例胃癌患者的预后因素分析.中国肿瘤临床.2006,33(7)：399-402.
3. Piessen G, Messager M, Leteurtre E, et al. Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation. Ann Surg.2009, 250(6):878-887.
4. Li C, Kim S, Lai JF, et al. Advanced gastric carcinoma with signet ring cell histology. Oncology.2007,72(1-2):64-68.
5. Nakamura K, Ozaki N, Yamada T, et al. Evaluation of prognostic significance in extracapsular spread of lymph node metastasis in patients with gastric cancer. Surgery.2005,137(5):511-517.
6. Al-Moundhri MS, Al-Bahrani B, Burney IA, et al. The prognostic determinants of gastric cancer treatment outcome in Omani Arab patients. Oncology.2006,70(2):90-96.
7. Lee WS, Song HS, Kim IH, et al. Prognostic significance of Lauren classification in curatively resected gastric cancer. Proc Am Soc Clin Oncol.22:2003(abstr 1453).
8. Hamilton S.R., Aaltonen L.A. (Eds.):World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. IARC Press:Lyon 2000.
9. Marchet A, Mocellin S, Ambrosi A, et al. The prognostic value of N-ratio in patients with gastric cancer:validation in a large, multicenter series. Eur J Surg Oncol.2008,34(2):159-165.
10.许国强,倪晓莹,顾秀珍.1554例胃癌的临床分析.中国肿瘤临床.2002,29(7)：481-483.
11.柴宝,陈星,郭亚荣.胃癌1517例临床特征分析.山西医科大学学报,2009,40(10)：924-926.
12.袁建青,李兰英,赵明臻.青海地区近十年胃癌构成分析.世界华人 消化杂志.2007,15(15)：1763-1765.
13.梁寒,郝希山,王家仓等.青年人胃癌.中华胃肠外科杂志.2001,4(2)：85-87.
14. Yu J, Zhao Q. The demographic characteristics of histological types of gastric cancer with gender, age, and tumor location. J Gastrointest Cancer. 2009,40(3-4):98-100.
15. Park JC, Lee YC, Kim JH, et al. Clinicopathological aspects and prognostic value with respect to age:an analysis of 3,362 consecutive gastric cancer patients. J Surg Oncol.2009,99(7):395-401.
16. Smith JK, Mcphee JT, Hill JS, et al. National outcomes after gastric resection for neoplasm. Arch Surg.2007,142(4):387-393.
17. Borch K, Jonsson B, Tarpila E, et al. Changing pattern of histological type, location, stage and outcome of surgical treatment of gastric carcinoma. Br J Surg.2000,87(5):618-626.
18. Edwards P, Blackshaw GR, Lewis WG, et al. Prospective comparison of D1 vs modified D2 gastrectomy for carcinoma. Br J Cancer.2004, 90(10):1888-1892.
19. Cunningham SC, Kamangar F, Kim MP, et al. Survival after gastric adenocarcinoma resection:Eighteen-year experience at a single institution. J Gastrointest Surg.2005,9(5):718-725.
20. Degiuli M, Sasako M, Ponti A, et al. Survival results of a multicentre phase Ⅱ study to evaluate D2 gastrectomy for gastric cancer. Br J Cancer. 2004,90(9):1727-1732.
21. Lepage C, Sant M, Verdecchia A, et al. Operative mortality after gastric cancer resection and long-term survival differences across Europe. Br J Surg.2010,97(2):235-239.
22. Sano T, Sasako M, Yamamoto S, et al. Gastric cancer surgery:Morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended para-aorticlymphadenectomy-Japan Clinical Oncology Group study 9501. J Clin Oncol.2004,22(14):2767-2773.
23. Hidaka S, Tanaka K, Takeshita H, et al. Clinicopathology and prognosis of mucinous gastric carcinoma. Hepatogastroenterology.2008,55(82-83): 791-794.
24. Kunisaki C, Makino H, Takagawa R, et al. Tumor diameter as a prognostic factor in patients with gastric cancer. Ann Surg Oncol. 2008,15(7):1959-1967.
25. Orsenigo E, Carlucci M, Braga M, et al. Prognostic factors of gastric neoplasms:experience with 1,074 cases undergoing surgical treatment at a single center. Suppl Tumori.2005,4(3):S86-87.
26. Radovanovic D, Mitrovic N, Stevanovic D, et al. Tumor volume in advanced gastric cancer as a prognostic factor correlating with lymph node involvement. Med Pregl.2005,58(7-8):351-356.
27. Kim JP, Lee JH, Kim SJ, et al. Clinicopathologic characteristics and prognostic factors in 10 783 patients with gastric cancer. Gastric Cancer. 1998,1(2):125-133.
28. Casariego vales E, Pita fernandez S, Rigueiro veloso M T, et al. Supervivencia en 2334 pacientes con cancer gastrico y factores que modifican el pronostico, Med Clin (Barc).2001,117(10):361-365.
29. Lazar D, Taban S, Dema A, et al. Gastric cancer:the correlation between the clinicopathological factors and (Ⅰ). Rom J Morphol Embryol.2009,50(1):41-50.
30. Santoro R, Carboni F, Lepiane P, et al. Clinicopathological features and prognosis of gastric cancer in young European adults. Br J Surg.2007, 94(6):737-742.
31. Lee JH, Ryu KW, Lee JS, et al. Decisions for extent of gastric surgery in gastric cancer patients:younger patients require more attention than the elderly. J Surg Oncol.2007,95(6):485-490.
32. Kunisaki C, Akiyama H, Nomura M, et al. Clinicopathological features of gastric carcinoma in younger and middle-aged patients:a comparative study. J Gastrointest Surg.2006,10(7):1023-1032.
33. Saito H, Osaki T, Murakami D, et al. Effect of age on prognosis in patients with gastric cancer. ANZ J Surg.2006,76(6):458-461.
34. Park YK, Kim JC, Koh YS, et al. Early gastric carcinoma in young patients. Int Surg.2006,91(6):316-319.
35. Llanos O, Butte JM, Crovari F, et al. Survival of young patients after gastrectomy for gastric cancer. World J Surg.2006,30(1):17-20.
36. Kulig J, Popiela T, Kolodziejczyk P, et al. Clinicopathological profile and long-term outcome in young adults with gastric cancer:multicenter evaluation of 214 patients. Langenbecks Arch Surg.2008,393(1):37-43.
37. Smith BR, Stabile BE. Extreme aggressiveness and lethality of gastric adenocarcinoma in the very young. Arch Surg.2009,144(6):506-510.
38. Ichikawa D, Kubota T, Kikuchi S, et al. Prognostic impact of lymphatic invasion in patients with node-negative gastric cancer. J Surg Oncol. 2009,100(2):111-114.
39. del Casar JM, Corte MD, Alvarez A, et al. Lymphatic and/or blood vessel invasion in gastric cancer:relationship with clinicopathological parameters, biological factors and prognostic significance. J Cancer Res Clin Oncol.2008,134(2):153-161.
40. Lee CC, Wu CW, Lo SS, et al. Survival predictors in patients with node-negative gastric carcinoma. J Gastroenterol Hepatol.2007,22(7): 1014-1018.
41. Sobin L, Wittekind C:International Union Against Cancer (UICC):TNM classification of malignant tumors 6th edition. New York:Wiley; 2002.
42. Nitti D, Marchet A, Olivieri M, et al. Ratio between metastatic and examined lymph nodes is an independent prognostic factor after D2 resection for gastric cancer:analysis of a large European monoinstitutional experience. Ann Surg Oncol.2003,10(9):1077-1085.
43. Bando E, Yonemura Y, Taniguchi K, et al. Outcome of ratio of lymph node metastasis in gastric carcinoma. Ann Surg Oncol.2002,9(8): 775-784.
44. Inoue K, Nakane Y, Iiyama H, et al. The superiority of ratio-based lymph node staging in gastric carcinoma. Ann Surg Oncol.2002,9(1):27-34.
45. Liu C, Lu P, Lu Y, et al. Clinical implications of metastatic lymph node ratio in gastric cancer. BMC Cancer.2007,7:200-204.
46. Ozguc H, Sonmez Y, Yerci O. Metastatic/resected lymph nodes ratio-based classification in gastric cancer. Turk J Gastroenterol. 2008,19(1):2-7.
47. Hyung WJ, Noh SH, Yoo CH, et al. Prognostic significance of metastatic lymph node ratio in T3 gastric cancer. World J Surg.2002,26(3):323-329.
48. Kunisaki C, Shimada H, Nomura M, et al. Clinical impact of metastatic lymph node ratio in advanced gastric cancer. Anticancer Res. 2005,25(2B):1369-1375.
49. Rodriguez Santiago JM, Munoz E, Marti M, et al. Metastatic lymph node ratio as a prognostic factor in gastric cancer. Eur J Surg Oncol. 2005,31(l):59-66.
50. Marchet A, Mocellin S, Ambrosi A, et al. The ratio between metastatic and examined lymph nodes (N ratio) is an independent prognostic factor in gastric cancer regardless of the type of lymphadenectomy:results from an Italian multicentric study in 1,853 patients. Ann Surg.2007,245(4): 543-552.
51. Persiani R, Rausei S, Biondi A, et al. Ratio of metastatic lymph nodes: impact on staging and survival of gastric cancer. Eur J Surg Oncol. 2008,34(5):519-524.
52. Celen O, Yildirim E, Berberoglu U. Prognostic impact of positive lymph node ratio in gastric carcinoma. J Surg Oncol.2007,96(2):95-101.
53. Saito H, Fukumoto Y, Osaki T, et al. Prognostic significance of the ratio between metastatic and dissected lymph nodes (n ratio) in patients with advanced gastric cancer. J Surg Oncol.2008,97(2):132-135.
54. Ojima H, Araki K, Kato T, et al. Clinicopathological characteristics and outcome indicators of stage Ⅱ gastric cancer according to the Japanese classification of gastric cancer. Anticancer Res.2006,26(2B):1385-1390.
1. Rebischung C, Barnoud R, Stefani L, et al. The effectiveness of trastuzumab (herceptin) combined with chemotherapy for gastric carcinoma with overexpression of the c-erbB-2 protein. Gastric Cancer.2005,8(4):249-252.
2. Bang YJ, Chung HC, Xu JM, et al. Pathological features of advanced gastric cancer:relationship to human epidermal growth factor receptor 2 positivity in the global screening programme of the ToGA trial. J Clin Oncol.2009,27:15s, (suppl; abstr 4556).
3. Ono M, Kuwano M. Molecularmechanisms of epidermal growth factor receptor(EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res.2006,12(24):7242-7251.
4. Goueli BS, Janknecht R. Upregulation of the catalytic telomerase subunit by the transcription factor ER81 and oncogenic HER2/Neu, Ras, or Raf. Mol Cell Biol.2004,24(1):25-35.
5. Dowdy SC, Mariani A, Janknecht R. HER2/neu and TAK1-mediated up-regulation of the transforming growth factor-beta inhibitor Smad7 via the ETS protein ER81. J Biol Chem.2003,278(45):44377-44384.
6. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer:results from a validation study. Histopathology.2008,52(7): 797-805.
7. Gravalos C, Jimeno A. HER2 in gastric cancer:a new prognostic factor and a novel therapeutic target. Ann Oncol.2008,19(9):1523-1529.
8. Ross JS, McKenna BJ. The HER-2/neu oncogene in tumors of the gastrointestinal tract. Cancer Invest.2001,19(5):554-68.
9. Takehana T, Kunitomo K, Kono K, et al. Status of c-erbB-2 in gastric adenocarcinoma:a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay. Int J Cancer. 2002,98(6):833-837.
10. Varis A, Zaika A, Puolakkainen P, et al. Coamplified and overexpressed genes at ERBB2 locus in gastric cancer. Int J Cancer.2004,109(4):548-553.
11. Park DI, Yun JW, Park JH, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci.2006,51(8):1371-1379.
12. Kim MA, Jung EJ, Lee HS, et al. Evaluation of HER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Hum Pathol. 2007,38(9):1386-1393.
13. Satiroglu-Tufan NL, Bir F, Calli-Demirkan N. Investigation of HER-2 codon 655 single nucleotide polymorphism frequency and c-ErbB-2 protein expression alterations in gastric cancer patients. World J Gastroenterol. 2006,12(20):3283-7.
14.张修礼,孙自勤,刘晓峰.ERBB2在胃癌组织中过表达的研究.胃肠病学和肝病学杂志,2007,16(5)：451-452.
15. Nakajima M, Sawada H, Yamada Y, et al. The prognostic significance of amp(?)fication and overexpression of c-met and c-erbB-2 in human gastric carcinomas. Cancer.1999,85(9):1894-902.
16. Polkowski W, van Sandick JW, Offerhaus GJ, et al. Prognostic value of Lauren classification and c-erbB-2 oncogene overexpression in adenocarcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol.1999,6(3):290-7.
17. Kim MA, Jung EJ, Lee HS, et al. Evaluation of HER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Hum Pathol. 2007,38(9):1386-93.
18. Tanner M, Hollmen M, Junttila TT, et al. Amplification of HER-2 in gastric carcinoma:association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005,16(2):273-8.
19. Gurel S, Dolar E, Yerci O, et al. The relationship between c-erbB-2 oncogene expression and clinicopathological factors in gastric cancer. J Int Med Res. 1999,27(2):74-8.
20. Garcia I, Vizoso F, Martin A, et al. Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol.2003,10(3):234-241.
21. Ougolkov A, Yamashita K, Bilim V, et al. Abnormal expression of E-cadherin, beta-catenin, and c-erbB-2 in advanced gastric cancer:its association with liver metastasis. Int J Colorectal Dis.2003,18(2):160-166.
22. Tsugawa K, Yonemura Y, Hirono Y, et al. Amplification of the c-met, c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers: correlation to clinical features. Oncology.1998,55(5):475-81.
23. Allgayer H, Babic R, Gruetzner KU, et al. c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems. J Clin Oncol.2000,18(11):2201-9.
24. Xie SD, Xu CY, Shen JG, et al. HER2/neu protein expression in gastric cancer is associated with poor survival. Molecular Medicine reports. 2009,2:943-946.
25. Marx AH, Tharun L, Muth J, et al. HER-2 amplification is highly homogenous in gastric cancer. Hum Pathol.2009,40(6):769-77.
26. Barros-Silva JD, Leitao D, Afonso L, et al. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. Br J Cancer.2009,100(3):487-93.
1. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol.2003,15(6):740-746.
2. Hemavathy, K, Ashraf, SI and Ip YT. Snail/slug family of repressors:slowly going into the fast lane of development and cancer. Gene.2000,257(1):1-12.
3. Nieto, MA. The snail superfamily of zinc-finger transcription factors.Nat. Rev. Mol Cell Biol.2002,3(3):155-166..
4. Savagner P, Yamada KM, Thiery JP. The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J Cell Biol. 1997,137(6):1403-1419.
5. Kajita M, McClinic KN, Wade PA. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol. 2004,24(17):7559-7566.
6. Wu WS, Heinrichs S, Xu D,et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma.Cell.2005,123(4):641-653.
7.王齐全,魏小斌,郑健超.siRNA干扰Slug基因表达对胰腺癌BxPC-3细胞放射敏感性的影响.世界华人消化杂志,2009,17(11)：1079-1084.
8.欧树安,张克君,严明总,等.Slug-siRNA干扰Slug基因表达对胰腺癌的抑制作用.世界华人消化杂志.2009,17(17)：1713-1719.
9. Inoue A, Seidel MG, Wu W, et al. Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Cancer Cell.2002,2(4):279-288.
10. Perez-Losada J, Sanchez-Martin M, Perez-Caro M, et al. The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug. Oncogene.2003,22(27):4205-4211.
11. Chan AO. E-cadherin in gastric cancer. World J Gastroenterol. 2006,12(2):199-203.
12. Christofori G, Semb H. The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci.1999,24(2):73-76.
13. Van Aken E, De Wever O, Correia da Rocha A, et al. Defective E-cadherin/catenin complexes in human cancer. Virchows Arch. 2001,439(6):725-751.
14. Jethwa P, Naqvi M, Hardy RG, et al. Overexpression of Slug is associated with malignant progression of esophageal adenocarcinoma. World J Gastroenterol.2008,21;14(7):1044-1052.
15. Hajra, KM, Chen, DY, Fearon, ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res,2002,62(6):1613-1618.
16. Lopez D, Niu G, Huber P, et al. Tumor-induced upregulation of Twist, Snail, and Slug represses the activity of the human VE-cadherin promoter. Arch Biochem Biophys.2009,482(1-2):77-82.
17. Sugimachi K, Tanaka S, Kameyama T, et al. Transcriptional Repressor Snail and Progression of Human Hepatocellular Carcinoma. Clin Cancer Res. 2003,9(7):2657-64.
18. Bolos V, Peinado H, Perez-Moreno MA, et al. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions:a comparison with Snail and E47 repressors. J Cell Sci. 2003,116(Pt 3):499-511.
19. Berx G, Becker KF, Hofler H, et al. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat.1998,12(4):226-237.
20. Wang L, Zhang F, Wu PP, et al. Disordered beta-catenin expression and E-cadherin/CDH1 promoter methylation in gastric carcinoma. World J Gastroenterol.2006,12(26):4228-4231.
21. Zazula M, Ferreira AM, Czopek JP, et al. CDH1 gene promoter hypermethylation in gastric cancer:relationship to Goseki grading, microsatellite instability status, and EBV invasion. Diagn Mol Pathol. 2006,15(1):24-9.
22. Come C, Magnino F, Bibeau F, et al. Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res.2006,12(18):5395-5402.
23. Stemmler M, Hecht A, Kemler R. E-cadherin intron 2 contains cis-regulatory elements essential for gene expression. Development.2005,132(5):965-976.
24. Batsche E, Muchardt C, Behrens J, et al.RB and c-Myc activate expressionof the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2. Mol Cell Biol.1998,18(7):3647-3658.
25. Grady WM, Willis J, Guilford PJ, et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet. 2000,26(1):16-7.
26. Oliveira C, de Bruin J, Nabais S, et al. Intragenic deletion of CDH1 as the inactivating mechanism of the wild-type allele in an HDGC tumour. Oncogene.2004,23(12):2236-2240.
27. Lee TL, Leung WK, Chan MW, et al. Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma. Clin Can cer Res.2002,8(6):1761-1766.
28. Barber M, Murrell A, Ito Y, et al. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol.2008,216(3):295-306.
29. Humar B, Blair V, Charlton A, et al. E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man. Cancer Res. 2009,69(5):2050-2056.
30. Martin TA, Goyal A, Watkins G, et al. Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol.2005,12(6):488-496.
31. Uchikado Y, Natsugoe S, Okumura H, et al. Slug expression in the E-cadherin preserved tumors is related to prognosis in patients with esophageal squamous cell carcinoma. Clin Cancer Res.2005,11(3):1174-1180.
32. Shioiri M, Shida T, Koda K, et al. Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Br J Cancer.2006,94(2):1816-1822.
33. Shih JY, Tsai MF, Chang TH, et al. Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients1 with lung adenocarcinoma. Clin Cancer Res.2005;11(22):8070-8078.
34. Castro Alves C, Rosivatz E, Schott C, et al. Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. J Pathol.2007,211(5):507-515.
35. Hotz B, Arndt M, Dullat S, et al. Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. Clin Cancer Res.2007,13(16):4769-4776.
36. Cates JM, Byrd RH, Fohn LE, et al. Epithelial-mesenchymal transition markers in pancreatic ductal adenocarcinoma. Pancreas.2009,38(1):el-6.
37. Huntsman DG, Carneiro F, Lewis FR, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med 2001,344(25):1904-1909.
38. Suriano G, Oliveira MJ, Huntsman DG, et al. E-cadherin germline missense mutations and cell phenotype:evidence for the independence of cell invasion on the motile capabilities of the cells. Hum Mol Genet. 2003,12(22):3007-3016.
39. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature.1998,392(6674):402-405.
40. Gayther SA, Gorringe KL, Ramus SJ, et al. Identification of germ-line E-(?)dherin mutations in gastric cancer families of European origin. Cancer Res.1998,58(18):4086-4089.
41. Pedrazzani C, Corso, G, Marrelli, D, et al. E-cadherin and hereditary diffuse gastric cancer. Surgery.2007,142(5):645-657.
42. Yoon CS, Hyung WJ, Lee JH, et al. Expression of S100A4, E-cadherin, alpha-and beta-catenin in gastric adenocarcinoma. Hepatogastroenterology. 2008,55(86-87):1916-1920.
43. Arevalo F, Monge E, Morales D. E-cadherin molecular expresion in the diffuse and intestinal types of gastric adenocarcinoma. A report from Lima, Peru. Rev Esp Enferm Dig.2007,99(6):325-329.
44. Walch A, Seidl S, Hermannstadter C, et al. Combined analysis of Racl, IQGAP1, Tiaml and E-cadherin expression in gastric cancer. Mod Pathol. 2008,21(5):544-552.
45. Guzman P, Araya J, Villaseca M, et al. Immunohistochemical expression of the E-cadherin-catenin complex in gastric cancer Rev Med Chil. 2006,134(8):1002-1009.
46. Kim YD, Joo KJ, Park KY, et al. E-cadherin expression in early gastric carcinoma and correlation with lymph node metastasis. J Surg Oncol. 2007,96(5):429-435.
47. Aoki R, Yasuda M, Torisu R, et al. Relationship between lymph node metastasis and E-cadherin expression in submucosal invasive gastric carcinomas with gastric-phenotype. J Med Invest.2007,54(1-2):159-167.
48. Lee KH, Shin SJ, Kim KO, et al. Relationship between E-cadherin, matrix metalloproteinase-7 gene expression and clinicopathological features in gastric carcinoma. Oncol Rep.2006,16(4):823-830.
49. Zhong XY, Zhang LH, Jia SQ, et al. Positive association of up-regulated Cripto-1 and down-regulated E-cadherin with tumour progression and poor prognosis in gastric cancer. Histopathology.2008,52(5):560-568.
50. Kim JH, Park JM, Jung CW, et al. The significances of lymph node micrometastasis and its correlation with E-cadherin expression in pTl-T3N0 gastric adenocarcinoma. J Surg Oncol.2008,97(2):125-130.
51. Theuer CP, Al-Kuran R, Akiyama Y, et al. Increased epithelial cadherin expression among Japanese intestinal-type gastric cancers compared with specimens from American patients of European descent. Am Surg. 2006,72(4):332-338.
1. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006,12(3):354-362.
2. Henson DE, Dittus C, Younes M, et al. Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States,1973-2000:increase in the signet ring cell type. Arch Pathol Lab Med.2004,128(7):765-770.
3. Hamilton SR, Aaltonen LA. Pathology and Genetics of Tumours of the Digestive System. Lyon:IARC Press,2000:42-45.
4. Ekstrom AM, Serafini M, Nyren O, et al. Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: a population-based case-control study in Sweden. Int J Cancer. 2000,87(1):133-40.
5. Chan AO. E-cadherin in gastric cancer. World J Gastroenterol. 2006,12(2):199-203.
6. Yoon CS, Hyung WJ, Lee JH, et al. Expression of S100A4, E-cadherin, alpha-and beta-catenin in gastric adenocarcinoma. Hepatogastroenterology. 2008,55(86-87):1916-1920.
7. Arevalo F, Monge E, Morales D. E-cadherin molecular expresion in the diffuse and intestinal types of gastric adenocarcinoma. A report from Lima, Peru. Rev Esp Enferm Dig.2007,99(6):325-329.
8. Walch A, Seidl S, Hermannstadter C, et al. Combined analysis of Racl, IQGAP1, Tiaml and E-cadherin expression in gastric cancer. Mod Pathol. 2008,21(5):544-552.
9. Guzman P, Araya J, Villaseca M, et al. Immunohistochemical expression of the E-cadherin-catenin complex in gastric cancer Rev Med Chil. 2006,134(8):1002-1009.
10. Lee KH, Shin SJ, Kim KO, et al. Relationship between E-cadherin, matrix metalloproteinase-7 gene expression and clinicopathological features in gastric carcinoma. Oncol Rep.2006,16(4):823-830.
11. Zhong XY, Zhang LH, Jia SQ, et al. Positive association of up-regulated Cripto-1 and down-regulated E-cadherin with tumour progression and poor prognosis in gastric cancer. Histopathology.2008,52(5):560-568.
12. Kim JH, Park JM, Jung CW, et al. The significances of lymph node micrometastasis and its correlation with E-cadherin expression in pTl-T3N0 gastric adenocarcinoma. J Surg Oncol.2008,97(2):125-130.
13. Kim DY, Joo JK, Park YK, et al. E-cadherin expression in early gastric carcinoma and correlation with lymph node metastasis. J Surg Oncol. 2007,96(5):429-435.
14. Aoki R, Yasuda M, Torisu R, et al. Relationship between lymph node metastasis and E-cadherin expression in submucosal invasive gastric carcinomas with gastric-phenotype. J Med Invest.2007,54(1-2):159-167.
15. Boo YJ, Park SS, Kim JH, et al. Gastric neuroendocrine carcinoma: clinicopathologic review and immunohistochemical study of E-cadherin and Ki-67 as prognostic markers. J Surg Oncol.2007,95(2):110-117.
16. Theuer CP, Al-Kuran R, Akiyama Y, et al. Increased epithelial cadherin expression among Japanese intestinal-type gastric cancers compared with specimens from American patients of European descent. Am Surg. 2006,72(4):332-338.
17. Berx G, Becker KF, Hofler H, et al. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat.1998,12(4):226-237.
18. Costello JF, Plass C. Methylation matters. J Med Genet 2001,38(5):285-303
19. Wang L, Zhang F, Wu PP, et al. Disordered beta-catenin expression and E-cadherin/CDH1 promoter methylation in gastric carcinoma. World J Gastroenterol.2006,12(26):4228-4231.
20. Zazula M, Ferreira AM, Czopek JP, et al. CDH1 gene promoter hypermethylation in gastric cancer:relationship to Goseki grading, microsatellite instability status, and EBV invasion. Diagn Mol Pathol. 2006,15(1):24-29.
21. Ikoma H, Ichikawa D, Koike H, et al. Correlation between serum DNA methylation and prognosis in gastric cancer patients. Anticancer Res. 2006,26(3B):2313-2316.
22. Liu YC, Shen CY, Wu HS, et al. Mechanisms inactivating the gene for E-cadherin in sporadic gastric carcinomas. World J Gastroenterol. 2006,12(14):2168-2173.
23. Korpal M, Lee ES, Hu G, et al. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem.2008,283(22):14910-14914.
24. Nakada C, Matsuura K, Tsukamoto Y, et al. Genome-wide microRNA expression profiling in renal cell carcinoma:significant down-regulation of miR-141 and miR-200c. J Pathol.2008,216(4):418-427.
25. Gandellini P, Folini M, Longoni N, et al. miR-205 Exerts tumor-suppressive fu(?)ions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res.2009,69(6):2287-2295.
26. Park SM, Gaur AB, Lengyel E, et al. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev.2008,22(7):894-907.
27. Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol.2008,10(5):593-601.
28. Nakada C, Matsuura K, Tsukamoto Y, et al. Genome-wide microRNA expression profiling in renal cell carcinoma:significant down-regulation of miR-141 and miR-200c. J Pathol.2008,216(4):418-427.
29. Hurteau GJ, Carlson JA, Spivack SD, et al. Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res.2007,67(17):7972-7976.
30. Hurteau GJ, Carlson JA, Roos E, et al. Stable expression of miR-200c alone is sufficient to regulate TCF8 (ZEB1) and restore E-cadherin expression. Cell Cycle.2009,8(13):2064-2069.
31. Place RF, Li LC, Pookot D, et al. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA. 2008,105(5):1608-1613.
1. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006,12(3):354-362.
2. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002. CA Cancer J Clin.2005,55(2):74-108.
3. Wang XQ, Terry PD, Yan H. Review of salt consumption and stomach cancer risk:epidemiological and biological evidence. World J Gastroenterol.2009, 15(18):2204-2213.
4.孙秀娣,牧人,周有尚,等.中国胃癌死亡率20年变化情况分析及其发展趋势预测.中华肿瘤杂志.2004,26(1)：4-9.
5. Lauren, P. The two histological main types of gastric carcinoma:diffuse and so-called intestinal-type carcinoma. Acta Pathol Microbiol Scand.1965,64: 31-49.
6. Owen DA. The Stomach. In:Stenberg SS, Antonioli D, Carter D, Mills SE, Oberman HA, eds. Diagnostic Surgical Pathology.3rd ed. New York: Lippincott Williams and Wilkins,1999:1311-49.
7. Fenoglio-Preiser, Noffsinder AE, Stemmermann GN, et al. Gastroentestinal Pathology, an Aatlas and Text.2nd. Philadelphia-New York: Lippincott-Raven,1998.
8. Ming SC. Gastric carcinoma. A pathobiological classification. Cancer.1977, 39(6):2475-85.
9. Goseki N, Takizawa T, Koike M. Differences in the mode of the extension of gatric cancer classified by histological type:new histologic classification of gastric carcinoma. Gut.1992,33(5):606-612.
10. Cimerman M, Repse S, Jelenc F, et al. Comparison of Lauren's, Ming's and WHO histological classifications of gastric cancer as a prognostic factor for operated patients. Int Surg.1994,79(1):27-32.
11. Luebke T, Baldus SE, Grass G, et al. Histological grading in gastric cancer by Ming classification:correlation with histopathological subtypes, metastasis, and prognosis. World J Surg.2005,29(1l):1422-1427.
12. Lee WS, Song HS, Kim IH, et al. Prognostic significance of Lauren classification in curatively resected gastric cancer. Proc Am Soc Clin Oncol. 22:2003(abstr 1453).
13. Calli Demirkan N, Tuncyurek M, Ugur Ertan E, et al. Correlation of histological classifications of gastric carcinomas with location and prognosis. Gastroenterol Clin Biol.2002,26(6-7):610-5.
14. Liang B, Wang S, Zhu X Q et al. Increased expression of MAPKs and its upstream regulating signal in human gastric cancer. World J Gastroenterol. 2005,11(5):623-8.
15. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states:acquisition of malignant and stem cell traits. cancer.2009,9(4): 265-273.
16. Ono M, Kuwano M. Molecularmechanisms of epidermal growth factor receptor(EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res.2006,12(24):7242-7251.
17. Goueli BS, JanknechtR. Upregulation of the catalytic telomerase subunit by the transcription factor ER81and oncogenic HER2/Neu, Ras, or Raf. Mol Cell Biol.2004,24(1):25-35.
18. Dowdy SC, Mariani A, Janknecht R. HER2/neu and TAK1-mediated up-regulation of the transforming growth factor-beta inhibitor Smad7 via the ETS protein ER81. J Biol Chem.2003,278(45):44377-44384.
19. Finkenzeller G, Weindel K, Zimmermann W, et al. Activated Neu/ErbB-2 induces expression of the vascular endothelial growth factor gene by functional activation of the transcription factor Sp1. Angiogenesis. 2004,7(1):59-68.
20. Tanner M, Hollmen M, Junttila TT, et al. Amplification of HER-2 in gastric carcinoma:association with Topoisomerase Ⅱ alpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005,16(2):273-8.
21. Rebischung C, Barnoud R, Stefani L, et al. The effectiveness of trastuzumab (herceptin) combined with chemotherapy for gastric carcinoma with overexpression of the c-erbB-2 protein. Gastric Cancer.2005,8(4):249-252.
22. Boyer B, Valles AM, and Edme N. Induction and regulation of epithelial-mesenchymal transitions. Biochem Pharmacol.2000,60(8):1091-1099.
23. Thiery JP. Epithelial-mesenchymal transition in tumor progression. Nature Rev Cancer.2002,2:442-454.
1.赵刚,邱江锋,吴志勇.603例胃癌根治术的预后因素分析.中国癌症杂志.2007,17(7)：556-559.
2.李景武,梁寒,王晓娜.814例胃癌患者的预后因素分析.中国肿瘤临床.2006,33(7)：399-402.
3. Piessen G, Messager M, Leteurtre E, et al. Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation. Ann Surg.2009, 250(6):878-887.
4. Li C, Kim S, Lai JF, et al. Advanced gastric carcinoma with signet ring cell histology. Oncology.2007,72(1-2):64-68.
5. Nakamura K, Ozaki N, Yamada T, et al. Evaluation of prognostic significance in extracapsular spread of lymph node metastasis in patients with gastric cancer. Surgery.2005,137(5):511-517.
6. Al-Moundhri MS, Al-Bahrani B, Burney IA, et al. The prognostic determinants of gastric cancer treatment outcome in Omani Arab patients. Oncology.2006,70(2):90-96.
7. Lee WS, Song HS, Kim IH, et al. Prognostic significance of Lauren classification in curatively resected gastric cancer. Proc Am Soc Clin Oncol.22:2003(abstr 1453).
8. Hamilton S.R., Aaltonen L.A. (Eds.):World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Digestive System. IARC Press:Lyon 2000.
9. Marchet A, Mocellin S, Ambrosi A, et al. The prognostic value of N-ratio in patients with gastric cancer:validation in a large, multicenter series. Eur J Surg Oncol.2008,34(2):159-165.
10.许国强,倪晓莹,顾秀珍.1554例胃癌的临床分析.中国肿瘤临床.2002,29(7)：481-483.
11.柴宝,陈星,郭亚荣.胃癌1517例临床特征分析.山西医科大学学报,2009,40(10)：924-926.
12.袁建青,李兰英,赵明臻.青海地区近十年胃癌构成分析.世界华人 消化杂志.2007,15(15)：1763-1765.
13.梁寒,郝希山,王家仓等.青年人胃癌.中华胃肠外科杂志.2001,4(2)：85-87.
14. Yu J, Zhao Q. The demographic characteristics of histological types of gastric cancer with gender, age, and tumor location. J Gastrointest Cancer. 2009,40(3-4):98-100.
15. Park JC, Lee YC, Kim JH, et al. Clinicopathological aspects and prognostic value with respect to age:an analysis of 3,362 consecutive gastric cancer patients. J Surg Oncol.2009,99(7):395-401.
16. Smith JK, Mcphee JT, Hill JS, et al. National outcomes after gastric resection for neoplasm. Arch Surg.2007,142(4):387-393.
17. Borch K, Jonsson B, Tarpila E, et al. Changing pattern of histological type, location, stage and outcome of surgical treatment of gastric carcinoma. Br J Surg.2000,87(5):618-626.
18. Edwards P, Blackshaw GR, Lewis WG, et al. Prospective comparison of D1 vs modified D2 gastrectomy for carcinoma. Br J Cancer.2004, 90(10):1888-1892.
19. Cunningham SC, Kamangar F, Kim MP, et al. Survival after gastric adenocarcinoma resection:Eighteen-year experience at a single institution. J Gastrointest Surg.2005,9(5):718-725.
20. Degiuli M, Sasako M, Ponti A, et al. Survival results of a multicentre phase Ⅱ study to evaluate D2 gastrectomy for gastric cancer. Br J Cancer. 2004,90(9):1727-1732.
21. Lepage C, Sant M, Verdecchia A, et al. Operative mortality after gastric cancer resection and long-term survival differences across Europe. Br J Surg.2010,97(2):235-239.
22. Sano T, Sasako M, Yamamoto S, et al. Gastric cancer surgery:Morbidity and mortality results from a prospective randomized controlled trial comparing D2 and extended para-aorticlymphadenectomy-Japan Clinical Oncology Group study 9501. J Clin Oncol.2004,22(14):2767-2773.
23. Hidaka S, Tanaka K, Takeshita H, et al. Clinicopathology and prognosis of mucinous gastric carcinoma. Hepatogastroenterology.2008,55(82-83): 791-794.
24. Kunisaki C, Makino H, Takagawa R, et al. Tumor diameter as a prognostic factor in patients with gastric cancer. Ann Surg Oncol. 2008,15(7):1959-1967.
25. Orsenigo E, Carlucci M, Braga M, et al. Prognostic factors of gastric neoplasms:experience with 1,074 cases undergoing surgical treatment at a single center. Suppl Tumori.2005,4(3):S86-87.
26. Radovanovic D, Mitrovic N, Stevanovic D, et al. Tumor volume in advanced gastric cancer as a prognostic factor correlating with lymph node involvement. Med Pregl.2005,58(7-8):351-356.
27. Kim JP, Lee JH, Kim SJ, et al. Clinicopathologic characteristics and prognostic factors in 10 783 patients with gastric cancer. Gastric Cancer. 1998,1(2):125-133.
28. Casariego vales E, Pita fernandez S, Rigueiro veloso M T, et al. Supervivencia en 2334 pacientes con cancer gastrico y factores que modifican el pronostico, Med Clin (Barc).2001,117(10):361-365.
29. Lazar D, Taban S, Dema A, et al. Gastric cancer:the correlation between the clinicopathological factors and (Ⅰ). Rom J Morphol Embryol.2009,50(1):41-50.
30. Santoro R, Carboni F, Lepiane P, et al. Clinicopathological features and prognosis of gastric cancer in young European adults. Br J Surg.2007, 94(6):737-742.
31. Lee JH, Ryu KW, Lee JS, et al. Decisions for extent of gastric surgery in gastric cancer patients:younger patients require more attention than the elderly. J Surg Oncol.2007,95(6):485-490.
32. Kunisaki C, Akiyama H, Nomura M, et al. Clinicopathological features of gastric carcinoma in younger and middle-aged patients:a comparative study. J Gastrointest Surg.2006,10(7):1023-1032.
33. Saito H, Osaki T, Murakami D, et al. Effect of age on prognosis in patients with gastric cancer. ANZ J Surg.2006,76(6):458-461.
34. Park YK, Kim JC, Koh YS, et al. Early gastric carcinoma in young patients. Int Surg.2006,91(6):316-319.
35. Llanos O, Butte JM, Crovari F, et al. Survival of young patients after gastrectomy for gastric cancer. World J Surg.2006,30(1):17-20.
36. Kulig J, Popiela T, Kolodziejczyk P, et al. Clinicopathological profile and long-term outcome in young adults with gastric cancer:multicenter evaluation of 214 patients. Langenbecks Arch Surg.2008,393(1):37-43.
37. Smith BR, Stabile BE. Extreme aggressiveness and lethality of gastric adenocarcinoma in the very young. Arch Surg.2009,144(6):506-510.
38. Ichikawa D, Kubota T, Kikuchi S, et al. Prognostic impact of lymphatic invasion in patients with node-negative gastric cancer. J Surg Oncol. 2009,100(2):111-114.
39. del Casar JM, Corte MD, Alvarez A, et al. Lymphatic and/or blood vessel invasion in gastric cancer:relationship with clinicopathological parameters, biological factors and prognostic significance. J Cancer Res Clin Oncol.2008,134(2):153-161.
40. Lee CC, Wu CW, Lo SS, et al. Survival predictors in patients with node-negative gastric carcinoma. J Gastroenterol Hepatol.2007,22(7): 1014-1018.
41. Sobin L, Wittekind C:International Union Against Cancer (UICC):TNM classification of malignant tumors 6th edition. New York:Wiley; 2002.
42. Nitti D, Marchet A, Olivieri M, et al. Ratio between metastatic and examined lymph nodes is an independent prognostic factor after D2 resection for gastric cancer:analysis of a large European monoinstitutional experience. Ann Surg Oncol.2003,10(9):1077-1085.
43. Bando E, Yonemura Y, Taniguchi K, et al. Outcome of ratio of lymph node metastasis in gastric carcinoma. Ann Surg Oncol.2002,9(8): 775-784.
44. Inoue K, Nakane Y, Iiyama H, et al. The superiority of ratio-based lymph node staging in gastric carcinoma. Ann Surg Oncol.2002,9(1):27-34.
45. Liu C, Lu P, Lu Y, et al. Clinical implications of metastatic lymph node ratio in gastric cancer. BMC Cancer.2007,7:200-204.
46. Ozguc H, Sonmez Y, Yerci O. Metastatic/resected lymph nodes ratio-based classification in gastric cancer. Turk J Gastroenterol. 2008,19(1):2-7.
47. Hyung WJ, Noh SH, Yoo CH, et al. Prognostic significance of metastatic lymph node ratio in T3 gastric cancer. World J Surg.2002,26(3):323-329.
48. Kunisaki C, Shimada H, Nomura M, et al. Clinical impact of metastatic lymph node ratio in advanced gastric cancer. Anticancer Res. 2005,25(2B):1369-1375.
49. Rodriguez Santiago JM, Munoz E, Marti M, et al. Metastatic lymph node ratio as a prognostic factor in gastric cancer. Eur J Surg Oncol. 2005,31(l):59-66.
50. Marchet A, Mocellin S, Ambrosi A, et al. The ratio between metastatic and examined lymph nodes (N ratio) is an independent prognostic factor in gastric cancer regardless of the type of lymphadenectomy:results from an Italian multicentric study in 1,853 patients. Ann Surg.2007,245(4): 543-552.
51. Persiani R, Rausei S, Biondi A, et al. Ratio of metastatic lymph nodes: impact on staging and survival of gastric cancer. Eur J Surg Oncol. 2008,34(5):519-524.
52. Celen O, Yildirim E, Berberoglu U. Prognostic impact of positive lymph node ratio in gastric carcinoma. J Surg Oncol.2007,96(2):95-101.
53. Saito H, Fukumoto Y, Osaki T, et al. Prognostic significance of the ratio between metastatic and dissected lymph nodes (n ratio) in patients with advanced gastric cancer. J Surg Oncol.2008,97(2):132-135.
54. Ojima H, Araki K, Kato T, et al. Clinicopathological characteristics and outcome indicators of stage Ⅱ gastric cancer according to the Japanese classification of gastric cancer. Anticancer Res.2006,26(2B):1385-1390.
1. Rebischung C, Barnoud R, Stefani L, et al. The effectiveness of trastuzumab (herceptin) combined with chemotherapy for gastric carcinoma with overexpression of the c-erbB-2 protein. Gastric Cancer.2005,8(4):249-252.
2. Bang YJ, Chung HC, Xu JM, et al. Pathological features of advanced gastric cancer:relationship to human epidermal growth factor receptor 2 positivity in the global screening programme of the ToGA trial. J Clin Oncol.2009,27:15s, (suppl; abstr 4556).
3. Ono M, Kuwano M. Molecularmechanisms of epidermal growth factor receptor(EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res.2006,12(24):7242-7251.
4. Goueli BS, Janknecht R. Upregulation of the catalytic telomerase subunit by the transcription factor ER81 and oncogenic HER2/Neu, Ras, or Raf. Mol Cell Biol.2004,24(1):25-35.
5. Dowdy SC, Mariani A, Janknecht R. HER2/neu and TAK1-mediated up-regulation of the transforming growth factor-beta inhibitor Smad7 via the ETS protein ER81. J Biol Chem.2003,278(45):44377-44384.
6. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer:results from a validation study. Histopathology.2008,52(7): 797-805.
7. Gravalos C, Jimeno A. HER2 in gastric cancer:a new prognostic factor and a novel therapeutic target. Ann Oncol.2008,19(9):1523-1529.
8. Ross JS, McKenna BJ. The HER-2/neu oncogene in tumors of the gastrointestinal tract. Cancer Invest.2001,19(5):554-68.
9. Takehana T, Kunitomo K, Kono K, et al. Status of c-erbB-2 in gastric adenocarcinoma:a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay. Int J Cancer. 2002,98(6):833-837.
10. Varis A, Zaika A, Puolakkainen P, et al. Coamplified and overexpressed genes at ERBB2 locus in gastric cancer. Int J Cancer.2004,109(4):548-553.
11. Park DI, Yun JW, Park JH, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci.2006,51(8):1371-1379.
12. Kim MA, Jung EJ, Lee HS, et al. Evaluation of HER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Hum Pathol. 2007,38(9):1386-1393.
13. Satiroglu-Tufan NL, Bir F, Calli-Demirkan N. Investigation of HER-2 codon 655 single nucleotide polymorphism frequency and c-ErbB-2 protein expression alterations in gastric cancer patients. World J Gastroenterol. 2006,12(20):3283-7.
14.张修礼,孙自勤,刘晓峰.ERBB2在胃癌组织中过表达的研究.胃肠病学和肝病学杂志,2007,16(5)：451-452.
15. Nakajima M, Sawada H, Yamada Y, et al. The prognostic significance of amp(?)fication and overexpression of c-met and c-erbB-2 in human gastric carcinomas. Cancer.1999,85(9):1894-902.
16. Polkowski W, van Sandick JW, Offerhaus GJ, et al. Prognostic value of Lauren classification and c-erbB-2 oncogene overexpression in adenocarcinoma of the esophagus and gastroesophageal junction. Ann Surg Oncol.1999,6(3):290-7.
17. Kim MA, Jung EJ, Lee HS, et al. Evaluation of HER-2 gene status in gastric carcinoma using immunohistochemistry, fluorescence in situ hybridization, and real-time quantitative polymerase chain reaction. Hum Pathol. 2007,38(9):1386-93.
18. Tanner M, Hollmen M, Junttila TT, et al. Amplification of HER-2 in gastric carcinoma:association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005,16(2):273-8.
19. Gurel S, Dolar E, Yerci O, et al. The relationship between c-erbB-2 oncogene expression and clinicopathological factors in gastric cancer. J Int Med Res. 1999,27(2):74-8.
20. Garcia I, Vizoso F, Martin A, et al. Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer. Ann Surg Oncol.2003,10(3):234-241.
21. Ougolkov A, Yamashita K, Bilim V, et al. Abnormal expression of E-cadherin, beta-catenin, and c-erbB-2 in advanced gastric cancer:its association with liver metastasis. Int J Colorectal Dis.2003,18(2):160-166.
22. Tsugawa K, Yonemura Y, Hirono Y, et al. Amplification of the c-met, c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers: correlation to clinical features. Oncology.1998,55(5):475-81.
23. Allgayer H, Babic R, Gruetzner KU, et al. c-erbB-2 is of independent prognostic relevance in gastric cancer and is associated with the expression of tumor-associated protease systems. J Clin Oncol.2000,18(11):2201-9.
24. Xie SD, Xu CY, Shen JG, et al. HER2/neu protein expression in gastric cancer is associated with poor survival. Molecular Medicine reports. 2009,2:943-946.
25. Marx AH, Tharun L, Muth J, et al. HER-2 amplification is highly homogenous in gastric cancer. Hum Pathol.2009,40(6):769-77.
26. Barros-Silva JD, Leitao D, Afonso L, et al. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. Br J Cancer.2009,100(3):487-93.
1. Thiery JP. Epithelial-mesenchymal transitions in development and pathologies. Curr Opin Cell Biol.2003,15(6):740-746.
2. Hemavathy, K, Ashraf, SI and Ip YT. Snail/slug family of repressors:slowly going into the fast lane of development and cancer. Gene.2000,257(1):1-12.
3. Nieto, MA. The snail superfamily of zinc-finger transcription factors.Nat. Rev. Mol Cell Biol.2002,3(3):155-166..
4. Savagner P, Yamada KM, Thiery JP. The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. J Cell Biol. 1997,137(6):1403-1419.
5. Kajita M, McClinic KN, Wade PA. Aberrant expression of the transcription factors snail and slug alters the response to genotoxic stress. Mol Cell Biol. 2004,24(17):7559-7566.
6. Wu WS, Heinrichs S, Xu D,et al. Slug antagonizes p53-mediated apoptosis of hematopoietic progenitors by repressing puma.Cell.2005,123(4):641-653.
7.王齐全,魏小斌,郑健超.siRNA干扰Slug基因表达对胰腺癌BxPC-3细胞放射敏感性的影响.世界华人消化杂志,2009,17(11)：1079-1084.
8.欧树安,张克君,严明总,等.Slug-siRNA干扰Slug基因表达对胰腺癌的抑制作用.世界华人消化杂志.2009,17(17)：1713-1719.
9. Inoue A, Seidel MG, Wu W, et al. Slug, a highly conserved zinc finger transcriptional repressor, protects hematopoietic progenitor cells from radiation-induced apoptosis in vivo. Cancer Cell.2002,2(4):279-288.
10. Perez-Losada J, Sanchez-Martin M, Perez-Caro M, et al. The radioresistance biological function of the SCF/kit signaling pathway is mediated by the zinc-finger transcription factor Slug. Oncogene.2003,22(27):4205-4211.
11. Chan AO. E-cadherin in gastric cancer. World J Gastroenterol. 2006,12(2):199-203.
12. Christofori G, Semb H. The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci.1999,24(2):73-76.
13. Van Aken E, De Wever O, Correia da Rocha A, et al. Defective E-cadherin/catenin complexes in human cancer. Virchows Arch. 2001,439(6):725-751.
14. Jethwa P, Naqvi M, Hardy RG, et al. Overexpression of Slug is associated with malignant progression of esophageal adenocarcinoma. World J Gastroenterol.2008,21;14(7):1044-1052.
15. Hajra, KM, Chen, DY, Fearon, ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res,2002,62(6):1613-1618.
16. Lopez D, Niu G, Huber P, et al. Tumor-induced upregulation of Twist, Snail, and Slug represses the activity of the human VE-cadherin promoter. Arch Biochem Biophys.2009,482(1-2):77-82.
17. Sugimachi K, Tanaka S, Kameyama T, et al. Transcriptional Repressor Snail and Progression of Human Hepatocellular Carcinoma. Clin Cancer Res. 2003,9(7):2657-64.
18. Bolos V, Peinado H, Perez-Moreno MA, et al. The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions:a comparison with Snail and E47 repressors. J Cell Sci. 2003,116(Pt 3):499-511.
19. Berx G, Becker KF, Hofler H, et al. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat.1998,12(4):226-237.
20. Wang L, Zhang F, Wu PP, et al. Disordered beta-catenin expression and E-cadherin/CDH1 promoter methylation in gastric carcinoma. World J Gastroenterol.2006,12(26):4228-4231.
21. Zazula M, Ferreira AM, Czopek JP, et al. CDH1 gene promoter hypermethylation in gastric cancer:relationship to Goseki grading, microsatellite instability status, and EBV invasion. Diagn Mol Pathol. 2006,15(1):24-9.
22. Come C, Magnino F, Bibeau F, et al. Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res.2006,12(18):5395-5402.
23. Stemmler M, Hecht A, Kemler R. E-cadherin intron 2 contains cis-regulatory elements essential for gene expression. Development.2005,132(5):965-976.
24. Batsche E, Muchardt C, Behrens J, et al.RB and c-Myc activate expressionof the E-cadherin gene in epithelial cells through interaction with transcription factor AP-2. Mol Cell Biol.1998,18(7):3647-3658.
25. Grady WM, Willis J, Guilford PJ, et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet. 2000,26(1):16-7.
26. Oliveira C, de Bruin J, Nabais S, et al. Intragenic deletion of CDH1 as the inactivating mechanism of the wild-type allele in an HDGC tumour. Oncogene.2004,23(12):2236-2240.
27. Lee TL, Leung WK, Chan MW, et al. Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma. Clin Can cer Res.2002,8(6):1761-1766.
28. Barber M, Murrell A, Ito Y, et al. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol.2008,216(3):295-306.
29. Humar B, Blair V, Charlton A, et al. E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man. Cancer Res. 2009,69(5):2050-2056.
30. Martin TA, Goyal A, Watkins G, et al. Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol.2005,12(6):488-496.
31. Uchikado Y, Natsugoe S, Okumura H, et al. Slug expression in the E-cadherin preserved tumors is related to prognosis in patients with esophageal squamous cell carcinoma. Clin Cancer Res.2005,11(3):1174-1180.
32. Shioiri M, Shida T, Koda K, et al. Slug expression is an independent prognostic parameter for poor survival in colorectal carcinoma patients. Br J Cancer.2006,94(2):1816-1822.
33. Shih JY, Tsai MF, Chang TH, et al. Transcription repressor slug promotes carcinoma invasion and predicts outcome of patients1 with lung adenocarcinoma. Clin Cancer Res.2005;11(22):8070-8078.
34. Castro Alves C, Rosivatz E, Schott C, et al. Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. J Pathol.2007,211(5):507-515.
35. Hotz B, Arndt M, Dullat S, et al. Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. Clin Cancer Res.2007,13(16):4769-4776.
36. Cates JM, Byrd RH, Fohn LE, et al. Epithelial-mesenchymal transition markers in pancreatic ductal adenocarcinoma. Pancreas.2009,38(1):el-6.
37. Huntsman DG, Carneiro F, Lewis FR, et al. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med 2001,344(25):1904-1909.
38. Suriano G, Oliveira MJ, Huntsman DG, et al. E-cadherin germline missense mutations and cell phenotype:evidence for the independence of cell invasion on the motile capabilities of the cells. Hum Mol Genet. 2003,12(22):3007-3016.
39. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature.1998,392(6674):402-405.
40. Gayther SA, Gorringe KL, Ramus SJ, et al. Identification of germ-line E-(?)dherin mutations in gastric cancer families of European origin. Cancer Res.1998,58(18):4086-4089.
41. Pedrazzani C, Corso, G, Marrelli, D, et al. E-cadherin and hereditary diffuse gastric cancer. Surgery.2007,142(5):645-657.
42. Yoon CS, Hyung WJ, Lee JH, et al. Expression of S100A4, E-cadherin, alpha-and beta-catenin in gastric adenocarcinoma. Hepatogastroenterology. 2008,55(86-87):1916-1920.
43. Arevalo F, Monge E, Morales D. E-cadherin molecular expresion in the diffuse and intestinal types of gastric adenocarcinoma. A report from Lima, Peru. Rev Esp Enferm Dig.2007,99(6):325-329.
44. Walch A, Seidl S, Hermannstadter C, et al. Combined analysis of Racl, IQGAP1, Tiaml and E-cadherin expression in gastric cancer. Mod Pathol. 2008,21(5):544-552.
45. Guzman P, Araya J, Villaseca M, et al. Immunohistochemical expression of the E-cadherin-catenin complex in gastric cancer Rev Med Chil. 2006,134(8):1002-1009.
46. Kim YD, Joo KJ, Park KY, et al. E-cadherin expression in early gastric carcinoma and correlation with lymph node metastasis. J Surg Oncol. 2007,96(5):429-435.
47. Aoki R, Yasuda M, Torisu R, et al. Relationship between lymph node metastasis and E-cadherin expression in submucosal invasive gastric carcinomas with gastric-phenotype. J Med Invest.2007,54(1-2):159-167.
48. Lee KH, Shin SJ, Kim KO, et al. Relationship between E-cadherin, matrix metalloproteinase-7 gene expression and clinicopathological features in gastric carcinoma. Oncol Rep.2006,16(4):823-830.
49. Zhong XY, Zhang LH, Jia SQ, et al. Positive association of up-regulated Cripto-1 and down-regulated E-cadherin with tumour progression and poor prognosis in gastric cancer. Histopathology.2008,52(5):560-568.
50. Kim JH, Park JM, Jung CW, et al. The significances of lymph node micrometastasis and its correlation with E-cadherin expression in pTl-T3N0 gastric adenocarcinoma. J Surg Oncol.2008,97(2):125-130.
51. Theuer CP, Al-Kuran R, Akiyama Y, et al. Increased epithelial cadherin expression among Japanese intestinal-type gastric cancers compared with specimens from American patients of European descent. Am Surg. 2006,72(4):332-338.
1. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006,12(3):354-362.
2. Henson DE, Dittus C, Younes M, et al. Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States,1973-2000:increase in the signet ring cell type. Arch Pathol Lab Med.2004,128(7):765-770.
3. Hamilton SR, Aaltonen LA. Pathology and Genetics of Tumours of the Digestive System. Lyon:IARC Press,2000:42-45.
4. Ekstrom AM, Serafini M, Nyren O, et al. Dietary antioxidant intake and the risk of cardia cancer and noncardia cancer of the intestinal and diffuse types: a population-based case-control study in Sweden. Int J Cancer. 2000,87(1):133-40.
5. Chan AO. E-cadherin in gastric cancer. World J Gastroenterol. 2006,12(2):199-203.
6. Yoon CS, Hyung WJ, Lee JH, et al. Expression of S100A4, E-cadherin, alpha-and beta-catenin in gastric adenocarcinoma. Hepatogastroenterology. 2008,55(86-87):1916-1920.
7. Arevalo F, Monge E, Morales D. E-cadherin molecular expresion in the diffuse and intestinal types of gastric adenocarcinoma. A report from Lima, Peru. Rev Esp Enferm Dig.2007,99(6):325-329.
8. Walch A, Seidl S, Hermannstadter C, et al. Combined analysis of Racl, IQGAP1, Tiaml and E-cadherin expression in gastric cancer. Mod Pathol. 2008,21(5):544-552.
9. Guzman P, Araya J, Villaseca M, et al. Immunohistochemical expression of the E-cadherin-catenin complex in gastric cancer Rev Med Chil. 2006,134(8):1002-1009.
10. Lee KH, Shin SJ, Kim KO, et al. Relationship between E-cadherin, matrix metalloproteinase-7 gene expression and clinicopathological features in gastric carcinoma. Oncol Rep.2006,16(4):823-830.
11. Zhong XY, Zhang LH, Jia SQ, et al. Positive association of up-regulated Cripto-1 and down-regulated E-cadherin with tumour progression and poor prognosis in gastric cancer. Histopathology.2008,52(5):560-568.
12. Kim JH, Park JM, Jung CW, et al. The significances of lymph node micrometastasis and its correlation with E-cadherin expression in pTl-T3N0 gastric adenocarcinoma. J Surg Oncol.2008,97(2):125-130.
13. Kim DY, Joo JK, Park YK, et al. E-cadherin expression in early gastric carcinoma and correlation with lymph node metastasis. J Surg Oncol. 2007,96(5):429-435.
14. Aoki R, Yasuda M, Torisu R, et al. Relationship between lymph node metastasis and E-cadherin expression in submucosal invasive gastric carcinomas with gastric-phenotype. J Med Invest.2007,54(1-2):159-167.
15. Boo YJ, Park SS, Kim JH, et al. Gastric neuroendocrine carcinoma: clinicopathologic review and immunohistochemical study of E-cadherin and Ki-67 as prognostic markers. J Surg Oncol.2007,95(2):110-117.
16. Theuer CP, Al-Kuran R, Akiyama Y, et al. Increased epithelial cadherin expression among Japanese intestinal-type gastric cancers compared with specimens from American patients of European descent. Am Surg. 2006,72(4):332-338.
17. Berx G, Becker KF, Hofler H, et al. Mutations of the human E-cadherin (CDH1) gene. Hum Mutat.1998,12(4):226-237.
18. Costello JF, Plass C. Methylation matters. J Med Genet 2001,38(5):285-303
19. Wang L, Zhang F, Wu PP, et al. Disordered beta-catenin expression and E-cadherin/CDH1 promoter methylation in gastric carcinoma. World J Gastroenterol.2006,12(26):4228-4231.
20. Zazula M, Ferreira AM, Czopek JP, et al. CDH1 gene promoter hypermethylation in gastric cancer:relationship to Goseki grading, microsatellite instability status, and EBV invasion. Diagn Mol Pathol. 2006,15(1):24-29.
21. Ikoma H, Ichikawa D, Koike H, et al. Correlation between serum DNA methylation and prognosis in gastric cancer patients. Anticancer Res. 2006,26(3B):2313-2316.
22. Liu YC, Shen CY, Wu HS, et al. Mechanisms inactivating the gene for E-cadherin in sporadic gastric carcinomas. World J Gastroenterol. 2006,12(14):2168-2173.
23. Korpal M, Lee ES, Hu G, et al. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J Biol Chem.2008,283(22):14910-14914.
24. Nakada C, Matsuura K, Tsukamoto Y, et al. Genome-wide microRNA expression profiling in renal cell carcinoma:significant down-regulation of miR-141 and miR-200c. J Pathol.2008,216(4):418-427.
25. Gandellini P, Folini M, Longoni N, et al. miR-205 Exerts tumor-suppressive fu(?)ions in human prostate through down-regulation of protein kinase Cepsilon. Cancer Res.2009,69(6):2287-2295.
26. Park SM, Gaur AB, Lengyel E, et al. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev.2008,22(7):894-907.
27. Gregory PA, Bert AG, Paterson EL, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol.2008,10(5):593-601.
28. Nakada C, Matsuura K, Tsukamoto Y, et al. Genome-wide microRNA expression profiling in renal cell carcinoma:significant down-regulation of miR-141 and miR-200c. J Pathol.2008,216(4):418-427.
29. Hurteau GJ, Carlson JA, Spivack SD, et al. Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res.2007,67(17):7972-7976.
30. Hurteau GJ, Carlson JA, Roos E, et al. Stable expression of miR-200c alone is sufficient to regulate TCF8 (ZEB1) and restore E-cadherin expression. Cell Cycle.2009,8(13):2064-2069.
31. Place RF, Li LC, Pookot D, et al. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proc Natl Acad Sci USA. 2008,105(5):1608-1613.