Notch1-4及Jagged1在肝细胞肝癌组织的表达
摘要
目的:Notch信号通路是一个在进化中高度保守的反映细胞间通讯机制的通路,它调控细胞的增殖、分化和凋亡,在胚胎发育和细胞命运的决定中发挥重要作用。Notch信号通路在不同组织细胞中作用不同,甚至在同一组织细胞的不同发展阶段作用也不同,这种生理作用依赖于细胞所处的环境。Notch信号不仅对正常细胞分化起重要作用,在肿瘤的形成中所起的重要作用已成为近年来研究的热点问题,但Notch信号在肝癌形成过程的机制,目前尚不十分清楚。本实验研究Notch信号配体分子Notch1-4和Jagged1在肝细胞癌、癌旁硬化肝组织及正常肝组织中的表达特点,并分析其与肝癌临床病理学参数的相关性,探讨这五种蛋白间的相关性。
方法:1研究对象:50例肝细胞癌癌组织、相对应50例癌旁硬化肝组织及12例肝血管瘤周边正常肝组织均来自河北医科大学第四医院肝胆外科2008年5月~2009年4月手术切除标本。所有组织类型均经河北医科大学第四医院病理科确诊。所有患者术前均未进行任何形式的治疗。
2研究方法:组织切除后经10%中性甲醛固定后石蜡包埋备用。应用免疫组织化学技术检测Notch1、Notch2、Notch3、Notch4及Jagged1在肝细胞癌癌组织、癌旁硬化肝组织及正常肝组织中的表达情况,分析染色强度在这三种肝组织的表达差异及其在临床病理学参数不同分组之间的差别。
结果: 1免疫组化结果显示所检测的Notch1分子在各组肝组织均有表达,Notch1表现为细胞浆黄染。Notch1在肝癌组织的表达显著高于癌旁硬化肝组织和正常肝组织(Z=-4.004, P=0.000和Z=-3.355,P=0.001),癌旁硬化肝组织表达和正常肝组织表达无统计学差异。Notch1在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无均无关;在肝癌病理分级高分化的癌组织中Notch1的表达强于低分化者(χ~2=6.938,P=0.031;r=-0.376,P=0.007);而Notch1的表达与肝癌临床分期无关。
2 Notch2在各组肝组织均有表达,表现为细胞浆黄染。Notch2在肝癌组织、癌旁硬化肝组织、正常肝组织,这三者之间的表达无统计学差异。Notch2在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无、肝癌临床分期及病理分级均无关。
3 Notch3在各组肝组织均有表达,表现为细胞浆黄染。Notch3在肝癌组织的表达显著高于癌旁硬化肝组织和正常肝组织(Z=-2.551, P=0.011和Z=-2.436,P=0.015),在癌旁硬化肝组织表达和正常肝组织表达无统计学差异。Notch3在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无均无关;在肝癌临床分期较晚的癌组织Notch3的表达强于分期较早者(χ~2=10.872,P=0.028;r=0.359,P=0.010);而Notch3的表达程度与肝癌病理分级无关。
4 Notch4在各组肝组织均有表达,表现为细胞浆黄染。Notch4在肝癌组织的表达显著高于癌旁硬化肝组织和正常肝组织(Z=-2.906, P=0.004和Z=-2.985,P=0.003),癌旁硬化肝组织表达和正常肝组织表达无统计学差异。Notch4在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无、肝癌临床分期及病理分级均无关。
5 Jagged1在各组肝组织均有表达,表现为细胞浆黄染。Jagged1在肝癌组织的表达显著高于癌旁硬化肝组织和正常肝组织(Z=-2.747, P=0.006和Z=-2.249,P=0.025),癌旁硬化肝组织表达和正常肝组织表达无统计学差异。Jagged1在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无、肝癌临床分期及病理分级均无关。
6肝癌组织中Notch1、Notch2、Notch3、Notch4与Jagged1表达情况的相关性:肝癌组织中Notch1与Notch2的表达无相关性(r=-0.003,P=0.981),与Notch3的表达无相关性(r=0.166,P=0.249)与Notch4的表达无相关性(r=0.184,P=0.200),与Jagged1的表达无相关性(r=-0.248,P=0.082),Notch2与Notch3的表达无相关性(r=-0.054,P=0.709),与Notch4的表达无相关性(r=0.137,P=0.344)与Jagged1的表达无相关性(r=0.144,P=0.317),Notch3与Notch4的表达无相关性(r=0.138,P=0.339),与Jagged1的表达无相关性(r=0.166,P=0.249),Notch4与Jagged1的表达无相关性(r=0.245,P=0.086)
结论:1 Notch1、Notch3、Notch4及Jagged1在肝细胞肝癌组织中的表达较癌旁硬化肝组织和正常肝组织升高,而在癌旁硬化肝组织和正常肝组织的表达无显著性差异。
2 Notch1在肝癌病理分级高分化的癌组织中的表达较低分化者升高; Notch3在肝癌临床分期较晚的癌组织的表达较分期较早者升高,提示Notch信号通路的异常激活可能与肝癌的发生发展有关。
Objective: Notch signaling pathway is an evolutionarily highly conserv- ed mechanism for cell-cell communication,which controls cell proliferation, differentiation,apoptosis,and plays an important role in embryogenesis and many types of cell fate determination.Notch signaling pathway has different function in different tissue cells and has different function at distinct stages of the same tissue cells.The biological function of this pathway is critically context dependent.Reports had showed that Notch signaling pathway is not only involved in the development of normal cells but also in cancer cells.Until now,the role of Notch signaling in HCC and its underlying mechanism are still unknown.To investigate the expression of Notch1-4 and Jagged1 in human hepatocellular carcinoma(HCC),adjacent non-cancerous cirrhotic hepatic tissue and normal hepatic tissue,we analyzed the association of their expression with clinicopathological parameters and the correlation among Notch1-4 and Jagged1.
Methods: 1 Samples collection follow up: 50 specimens of HCC,50 specimens of adjacent non-cancerous cirrhotic hepatic tissue and 12 specimens of normal hepatic tissue were obtained from the fourth hospital of Hebei Medical University,which were not treated before operation.
2 Imunostaining:The samples were fixed by 10% formaldehyde,embeded in paraffin after excision.Immunohistchemical staining was used to measure Notch1-4 and Jagged1 in HCC tissues and adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,the differences of clinicopathologi- cal groups for Immunohistochemical staining were analyzed by statistical methods.
Resluts: 1 Notch1 was expressed in HCC tissues,adjacent non-cancer- ous cirrhotic hepatic tissues,and normal hepatic tissues,which mostly expressed in cytoplasm.Notch1 expression in HCC tissue was much stronger than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue (Z=-4.004,P=0.000 and Z=-3.355,P=0.001),There was no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.Notch1 expression was significant stronger in better differentiation than that in poorer differentiation of HCC tissues (χ~2=6.938,P=0.031,r=-0.376,P=0.007).Notch1 expression in HCC tissues had showed no difference in different clinical stage.The Notch1 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope and the portal vein tumor thrombosis in HCC tissues based on our statistical analysis.
2 Notch2 was expressed in HCC tissues,adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,which mostly expressed in cytoplasm.Notch2 expression had no statistical difference among HCC tissue,adjacent non-cancerous cirrhotic hepatic tissue and normal hepatic tissue.The Notch2 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope,the portal vein tumor thrombosis,clinical stage,the pathological classification in HCC based on our statistical analysis.
3 Notch3 was expressed in HCC tissues,adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,which mostly expressed in cytoplasm.Notch3 expression in HCC tissue was much stronger than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue (Z=-2.551,P=0.011and Z=-2.436, P=0.015),There was no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.Notch3 expression was significant stronger in later clinical stage of HCC than earlier stage of HCC(χ~2=10.872,P=0.028,r=0.359, P=0.010), Notch3 expression showed no difference in different pathological classification of HCC. The Notch3 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope and the portal vein tumor thrombosis in HCC based on our statistical analysis.
4 Notch4 was expressed in HCC tissues,adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,which mostly expressed in cytoplasm.Notch4 expression in HCC tissue was much stronger than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue (Z=-2.906,P=0.004 and Z=-2.985,P=0.003),There was no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.The Notch4 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope,the portal vein tumor thrombosis,clinical stage,the pathological classification in HCC based on our statistical analysis.
5 Jagged1 was expressed in HCC tissues,adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,which mostly expressed in cytoplasm.Jagged1 expression in HCC tissue was much stronger than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue (Z=-2.747,P=0.006 and Z=-2.249,P=0.025),There was no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.The Jagged1 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope,the portal vein tumor thrombosis,clinical stage,the pathological classification in HCC based on our statistical analysis.
6 The correlation between Notch1,Notch2,Notch3,Notch4 and Jagged1 expression in HCC:Notch1 expression had no correlation with Notch2 expression level in HCC (r=-0.003,P=0.981),Notch1 expression level had no correlation with notch3 expression in HCC (r=0.166,P=0.249),Notch1 expression had no correlation with Notch4 expression level in HCC (r=0.184, P=0.200),Notch1 expression had no correlation with Jagged1 expression in HCC(r=-0.248,P=0.082),Noth2 expression had no correlation with Notch3 expression in HCC (r=-0.054, P=0.709),Notch2 expression had no correlation with Notch4 expression in HCC (r=0.137,P=0.344),Notch2 expression had no correlation with Jagged1 expression in HCC (r=0.144, P=0.317),Noth3 expressional level had no correlation with Notch4 expression in HCC (r=0.138,P=0.339),Noth3 expression had no correlation with Jagged1 expression in HCC (r=0.166,=0.249),Nothc4 expression had no correlation with Jagged1 expression in HCC (r=0.245,P=0.086).
Conclusions: 1 Notch1,Notch3,Notch4 and Jagged1 expression level in HCC tissue was much higher than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue,but had no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.
2 Notch1 expression level was significantly higher in better differentiation than poorer differentiation of HCC tissues,Notch3 expression level was significantly higher in later clinical stage of HCC than earlier stage,which showed that the abnormal activition of Notch signaling pathway might take effects on the progress of HCC.
方法:1研究对象:50例肝细胞癌癌组织、相对应50例癌旁硬化肝组织及12例肝血管瘤周边正常肝组织均来自河北医科大学第四医院肝胆外科2008年5月~2009年4月手术切除标本。所有组织类型均经河北医科大学第四医院病理科确诊。所有患者术前均未进行任何形式的治疗。
2研究方法:组织切除后经10%中性甲醛固定后石蜡包埋备用。应用免疫组织化学技术检测Notch1、Notch2、Notch3、Notch4及Jagged1在肝细胞癌癌组织、癌旁硬化肝组织及正常肝组织中的表达情况,分析染色强度在这三种肝组织的表达差异及其在临床病理学参数不同分组之间的差别。
结果: 1免疫组化结果显示所检测的Notch1分子在各组肝组织均有表达,Notch1表现为细胞浆黄染。Notch1在肝癌组织的表达显著高于癌旁硬化肝组织和正常肝组织(Z=-4.004, P=0.000和Z=-3.355,P=0.001),癌旁硬化肝组织表达和正常肝组织表达无统计学差异。Notch1在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无均无关;在肝癌病理分级高分化的癌组织中Notch1的表达强于低分化者(χ~2=6.938,P=0.031;r=-0.376,P=0.007);而Notch1的表达与肝癌临床分期无关。
2 Notch2在各组肝组织均有表达,表现为细胞浆黄染。Notch2在肝癌组织、癌旁硬化肝组织、正常肝组织,这三者之间的表达无统计学差异。Notch2在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无、肝癌临床分期及病理分级均无关。
3 Notch3在各组肝组织均有表达,表现为细胞浆黄染。Notch3在肝癌组织的表达显著高于癌旁硬化肝组织和正常肝组织(Z=-2.551, P=0.011和Z=-2.436,P=0.015),在癌旁硬化肝组织表达和正常肝组织表达无统计学差异。Notch3在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无均无关;在肝癌临床分期较晚的癌组织Notch3的表达强于分期较早者(χ~2=10.872,P=0.028;r=0.359,P=0.010);而Notch3的表达程度与肝癌病理分级无关。
4 Notch4在各组肝组织均有表达,表现为细胞浆黄染。Notch4在肝癌组织的表达显著高于癌旁硬化肝组织和正常肝组织(Z=-2.906, P=0.004和Z=-2.985,P=0.003),癌旁硬化肝组织表达和正常肝组织表达无统计学差异。Notch4在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无、肝癌临床分期及病理分级均无关。
5 Jagged1在各组肝组织均有表达,表现为细胞浆黄染。Jagged1在肝癌组织的表达显著高于癌旁硬化肝组织和正常肝组织(Z=-2.747, P=0.006和Z=-2.249,P=0.025),癌旁硬化肝组织表达和正常肝组织表达无统计学差异。Jagged1在肝癌组织的表达与患者性别、年龄、癌灶数目、肿瘤大小、AFP、HBsAg、HBeAg阴阳性、肿瘤包膜是否完整、瘤栓有无、肝癌临床分期及病理分级均无关。
6肝癌组织中Notch1、Notch2、Notch3、Notch4与Jagged1表达情况的相关性:肝癌组织中Notch1与Notch2的表达无相关性(r=-0.003,P=0.981),与Notch3的表达无相关性(r=0.166,P=0.249)与Notch4的表达无相关性(r=0.184,P=0.200),与Jagged1的表达无相关性(r=-0.248,P=0.082),Notch2与Notch3的表达无相关性(r=-0.054,P=0.709),与Notch4的表达无相关性(r=0.137,P=0.344)与Jagged1的表达无相关性(r=0.144,P=0.317),Notch3与Notch4的表达无相关性(r=0.138,P=0.339),与Jagged1的表达无相关性(r=0.166,P=0.249),Notch4与Jagged1的表达无相关性(r=0.245,P=0.086)
结论:1 Notch1、Notch3、Notch4及Jagged1在肝细胞肝癌组织中的表达较癌旁硬化肝组织和正常肝组织升高,而在癌旁硬化肝组织和正常肝组织的表达无显著性差异。
2 Notch1在肝癌病理分级高分化的癌组织中的表达较低分化者升高; Notch3在肝癌临床分期较晚的癌组织的表达较分期较早者升高,提示Notch信号通路的异常激活可能与肝癌的发生发展有关。
Objective: Notch signaling pathway is an evolutionarily highly conserv- ed mechanism for cell-cell communication,which controls cell proliferation, differentiation,apoptosis,and plays an important role in embryogenesis and many types of cell fate determination.Notch signaling pathway has different function in different tissue cells and has different function at distinct stages of the same tissue cells.The biological function of this pathway is critically context dependent.Reports had showed that Notch signaling pathway is not only involved in the development of normal cells but also in cancer cells.Until now,the role of Notch signaling in HCC and its underlying mechanism are still unknown.To investigate the expression of Notch1-4 and Jagged1 in human hepatocellular carcinoma(HCC),adjacent non-cancerous cirrhotic hepatic tissue and normal hepatic tissue,we analyzed the association of their expression with clinicopathological parameters and the correlation among Notch1-4 and Jagged1.
Methods: 1 Samples collection follow up: 50 specimens of HCC,50 specimens of adjacent non-cancerous cirrhotic hepatic tissue and 12 specimens of normal hepatic tissue were obtained from the fourth hospital of Hebei Medical University,which were not treated before operation.
2 Imunostaining:The samples were fixed by 10% formaldehyde,embeded in paraffin after excision.Immunohistchemical staining was used to measure Notch1-4 and Jagged1 in HCC tissues and adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,the differences of clinicopathologi- cal groups for Immunohistochemical staining were analyzed by statistical methods.
Resluts: 1 Notch1 was expressed in HCC tissues,adjacent non-cancer- ous cirrhotic hepatic tissues,and normal hepatic tissues,which mostly expressed in cytoplasm.Notch1 expression in HCC tissue was much stronger than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue (Z=-4.004,P=0.000 and Z=-3.355,P=0.001),There was no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.Notch1 expression was significant stronger in better differentiation than that in poorer differentiation of HCC tissues (χ~2=6.938,P=0.031,r=-0.376,P=0.007).Notch1 expression in HCC tissues had showed no difference in different clinical stage.The Notch1 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope and the portal vein tumor thrombosis in HCC tissues based on our statistical analysis.
2 Notch2 was expressed in HCC tissues,adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,which mostly expressed in cytoplasm.Notch2 expression had no statistical difference among HCC tissue,adjacent non-cancerous cirrhotic hepatic tissue and normal hepatic tissue.The Notch2 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope,the portal vein tumor thrombosis,clinical stage,the pathological classification in HCC based on our statistical analysis.
3 Notch3 was expressed in HCC tissues,adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,which mostly expressed in cytoplasm.Notch3 expression in HCC tissue was much stronger than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue (Z=-2.551,P=0.011and Z=-2.436, P=0.015),There was no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.Notch3 expression was significant stronger in later clinical stage of HCC than earlier stage of HCC(χ~2=10.872,P=0.028,r=0.359, P=0.010), Notch3 expression showed no difference in different pathological classification of HCC. The Notch3 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope and the portal vein tumor thrombosis in HCC based on our statistical analysis.
4 Notch4 was expressed in HCC tissues,adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,which mostly expressed in cytoplasm.Notch4 expression in HCC tissue was much stronger than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue (Z=-2.906,P=0.004 and Z=-2.985,P=0.003),There was no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.The Notch4 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope,the portal vein tumor thrombosis,clinical stage,the pathological classification in HCC based on our statistical analysis.
5 Jagged1 was expressed in HCC tissues,adjacent non-cancerous cirrhotic hepatic tissues and normal hepatic tissues,which mostly expressed in cytoplasm.Jagged1 expression in HCC tissue was much stronger than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue (Z=-2.747,P=0.006 and Z=-2.249,P=0.025),There was no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.The Jagged1 expression had no difference refered to sex,age,the number of tumor foci,size of tumor,AFP,HBsAg,HBeAg,the integrity of the tumor’s envelope,the portal vein tumor thrombosis,clinical stage,the pathological classification in HCC based on our statistical analysis.
6 The correlation between Notch1,Notch2,Notch3,Notch4 and Jagged1 expression in HCC:Notch1 expression had no correlation with Notch2 expression level in HCC (r=-0.003,P=0.981),Notch1 expression level had no correlation with notch3 expression in HCC (r=0.166,P=0.249),Notch1 expression had no correlation with Notch4 expression level in HCC (r=0.184, P=0.200),Notch1 expression had no correlation with Jagged1 expression in HCC(r=-0.248,P=0.082),Noth2 expression had no correlation with Notch3 expression in HCC (r=-0.054, P=0.709),Notch2 expression had no correlation with Notch4 expression in HCC (r=0.137,P=0.344),Notch2 expression had no correlation with Jagged1 expression in HCC (r=0.144, P=0.317),Noth3 expressional level had no correlation with Notch4 expression in HCC (r=0.138,P=0.339),Noth3 expression had no correlation with Jagged1 expression in HCC (r=0.166,=0.249),Nothc4 expression had no correlation with Jagged1 expression in HCC (r=0.245,P=0.086).
Conclusions: 1 Notch1,Notch3,Notch4 and Jagged1 expression level in HCC tissue was much higher than that in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue,but had no statistical difference existed between in adjacent non-cancerous cirrhotic hepatic tissue and in normal hepatic tissue.
2 Notch1 expression level was significantly higher in better differentiation than poorer differentiation of HCC tissues,Notch3 expression level was significantly higher in later clinical stage of HCC than earlier stage,which showed that the abnormal activition of Notch signaling pathway might take effects on the progress of HCC.
引文
1汤钊猷著.汤钊猷临床肝癌学.上海:上海科技教育出版社, 2001,24-25
2杨秉辉,夏景林.原发性肝癌的临床诊断与分期标准.中华肝脏病杂志, 2001, 9(6): 324
3 Li R,Younes M,Wheeler TM,et al.Expression of vascular endothelial growth factor receptor-3(VEGFR-3)in human prostate.Prostate,2004, 58(2):193-199
4 MC Cantarini,Smdela Monte,MPang,et al.Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Hepatology,2006,44(2):446-57
5 Roy M,Pear WS,Aster JC.The multifaceted role of Notch incancer. Curr Opin Genet Dev,2007,17(1):52-59
6董学斌,纪春岩,马道新,等.Notch信号在人类乳腺癌的作用.中华肿瘤学杂志, 2007, 29(6): 425-428
7 Tonon G,Modi S,Wu L,et al.t(11;19)(q21;p13) translocation inmucoep- idermoid carcinoma creates a novel fusion productthat disrupts a Notch signaling pathway.Nat Genet,2003,33(2):208-213
8 Nicolas M,Wolfer A,Raj K,et al.Notch1 functions as a tumor suppressor in mouse skin.Nat Genet,2003,33(33):416-421
9 Sriuranpong V,Borges MW,Ravi RK,et al.Notch signaling induces cell cycle arrest in small cell lung cancer cells.Cancer Res,2001,61(7): 3200-3205
10 Kerbel RS.Tumor angiogenesis: past,present and the near future. Carcinogenesis,2000, 21(3):505-515
11 Zagouras P,Stifani S,Blaumueller CM,et al.Alterations in Notchsignalingin neoplastic lesions of the human cervix. Proc Natl Acad Sci USA,1995, 92(14):6414-6418
12 Qi R,An H,Yu Y,et al.Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis.Cancer Res,2003,63(23): 8323 -8329
13 MC Cantarini,SM dela Monte,M Pang,etal.Aspartyl-aspa-ragyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Hepatology,2006,44(2):446-57
14 Nijjar SS,Crosby HA,Wallace L,et al.Notch receptor expression in adult human liver:apossible role in bile duct forma-tion and hepatic neovascularization.Hepatology,2001,34(6):118421192
15 Nijjar SS,Wallace L,Crosby HA,et al.Altered Notch ligand expression in human liver disease[J]. Am J of pathol,2002,160(5):1695-1703
16 Gramantieri L, Giovannini C, Lanzi A,et al.Aberrant Notch 3 and Notch4 expression in human hepatocellular carcinoma. Liver Int, 2007, 27(7): 997-1007
17杨志云,姚树坤,殷飞,等.清肝化瘀方对大鼠肝癌前病变模型Notch信号系统的影响.中医杂志,2006, 47(12):933-935
18徐洪雨,李宝杰,王瑞峰,等.Notch/Jagged信号在肝部分切除后肝再生中的表达.胃肠病学和肝病学杂志,2007,16(5):465-467
19 Gao J, Song Z, Chen Y,et al.Deregulated expression of No-receptors in human hepatocellular carcinoma [J]. Dig LiverDis,2008, 40(2): 114-121
20 Gao J, Chen C, HongL,etal.Expression ofJagged1 and itsassociationwith hepatitisB virusX protein in hepatocellular carcinoma.Biochem Biophys Res Commun, 2007, 356(2): 341-347.
21 Cantarini MC,Monte SM,Pang M,et al.Aspartly-aspa-ragyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and not-ch signaling mechanisms.Hepatology,2006,44(2):446-457
22 Chunmei Wang, Runzi Qi, Nan Li, et al. Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-indu-ing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 DDegradation and Up-regulating p53-dependent DR5 Expr-ession. Biological ehemistry,2009,284(24): 16183-16190
23 Miki A,Yano Y, KatoH,et al.Anti-tumor effect of pegylatedinterferon in the rat hepato carcinogenesis model. Int J Onco,2008, 32(3): 603-608
24 Kohler C, Bell AW, Bowen WC, et al. Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration. Hepatology, 2004,39(4):1056-65
25肖迎,王琪,鲁凤菊,等. Notch1蛋白在胚胎干细胞向神经细胞诱导分化过程中的表达及意义.山东医药,2007, 47(20):20-22
26徐洪雨,王瑞峰,李宝杰.Notch-1蛋白在诱导骨髓间充质干细胞向肝细胞分化中的表达.哈尔滨医科大学学报,2009,43(2):122-125
27 Kumano K,Chiba S,Shimizu K,et al.Notch1 inhibits diff-rentiation of hematopotetic cells by sustaining GATA-2 expression.Blood, 2001, 98:3283-3289
28 Zhang S,Balch C,Chan MW,et al.Identification and charac-terization of ovarian cancer–initiating cells from primary human tumors[J].Cancer Res,2008,68(11)43111-4320
29 Ma S,Chan KW,Hu L,et al.Identification and characteriza-tion of tumor genic liver cancer stem/progenitor cell[J].Gastroenterology, 2007,132(7): 2542-2556
30 Fan X,Matsui W,Khaki L,et al.Notch pathway inhibition Depletes stem-like cells and blocks engraftment in embryonal brain tumors.Cancer Res,2006,66(15):7445-7552
31龚加庆,方驰华,李雅.卵圆细胞参与实验性肝癌形成过程的研究.中华外科杂志,2004,42:291-295
32 Lowels,Kll,Bernnan BA,et al.Oval cell numbers in human chronic liver diseases are directly related to disease severity.Am J Pathol,1999, 154:537-541
33 Chi-hua Fnag,Wei-Zhang Xin,Yong Zhu, et al.The expression of c-kit and prolieferation cell nuclear antigen in oval cells of mice with hepa-tocellular carcimoma. Hepatobiliary Panceratic Dis Int.2003,2:481-487
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41 Saipin Suwanjunee, Wipawee Wongchana,Tanapat Palaga.Inhibition ofgamma-secretase affects proliferation of leukemia and hepatoma cell lines through Notch signaling. Anti-Cancer Drugs,2008(19):5477-5496
42 Xing-Bin Hu,Fan Feng,Yao-Chun Wang,et al.Blockade of notch signaling in tumor-bearing mice may lead to tumor regression, progression,or metastasis,depending on tumor cell types.Neoplasia,2009 ,11: 32-38
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44 Patel NS,Li JL,Generali D,et al.Up-regulation of Delta-like4 ligand in human tumor vasculature and the role of basal expression in endothelial cellfunction.Cancer Res,2005,65(19):8690-8697
45 Williams CK,Li JL,Murga M,et al.Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cellfunction.Blood, 2006,107(3):931-939
46 Croquelois A, Blindenbacher A, Terracciano L,et al.Inducible inactivation of Notch1 causes nodular regenerative hyperplasia in mice. Hepatology,2005,41(3): 487-496
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49 Sanne Weijzen , Paola Rizzo, Mike Braid ,et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nature Medicine,2002,8(9):979-986
50 Luke T. Krebs,1Yingzi Xue,Christine R.Norton,et al.Notch signaling is essential for vascular morphogenesis in mice.Genes& Development, 2000,23:1344-1350
51 Kiyoshi Shimizu,Shigeru Chiba,Toshiki Saito,et al.Func-tional Diversityamong Notch1, Notch2,and Notch3 Recep-tors. Biochemical and Biophysical Research Communica-tions,2002,291:775-779
52 Paul Beatus, Johan Lundkvist, Camilla Oberg, et al. The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity.Mechanisms of Delopment,2001,104:1-30
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40 Croquelois A, Blindenbacher A, Terracciano L,et al.Inducible inactivation of Notch1 causes nodular regenerative hyperplasia in mice. Hepatology, 2005, 41(3): 487-496
42 Qi R,An H,Yu Y,et al.Notch1 signaling inhibits growth of human he-hepatocellular carcinoma through induction of cell cycle arrest and apoptosis.Cancer Res,2003,63(23): 8323 -8329
43 Saipin Suwanjunee, Wipawee Wongchana,Tanapat Palaga.Inhibition ofgamma-secretase affects proliferation of leukemia and hepatoma cell lines through Notch signaling. Anti-Cancer Drugs,2008,23(19):5477-5496
44 Xing-Bin Hu, Fan Feng, Yao-Chun Wang,et al. Blockade of Notchsignaling in tumor-bearing mice may lead to tumor regression pro- gression, or metastasis,depending on tumor cell tupes.Bl Neoplasia, 2009,11: 32–38
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46 Patel NS,Li JL,Generali D,et al.Up-regulation of Delta-like4 ligand n human tumor vasculature and the role of basal expression in endothelial cellfunction.Cancer Res,2005,65(19):8690-8697
47 Williams CK,Li JL,Murga M,et al.Up-regulation of the Noch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function.Blood, 2006, 107(3):931-939
48 Giovannini C,Lacchini M,Gramantieri L,et al.Notch3 intracellular domain accumulates in HepG2 cell line.Anticancer Res,2006, 26(3A): 2123-7
49 Catia Giovannini,Laura Gramantieri,Pasquale Chieco,et al.Selective ablation of Notch3 in HCC enhances doxorubicin’s death promoting effect by a p53 dependent mechanism. Hepatology,2009,50:969-979
50 Sanne Weijzen,Paola Rizzo,Mike Braid,et al. Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells. Nature Medicine,2002,8(9):979-986
51 Luke T,Krebs,1Yingzi Xue,Christine R.Norton,et al.Notch signaling is essential for vascular morphogenesis in mice. Genes & Development,2000 ,23:1344-1350
52 Kiyoshi Shimizu,Shigeru Chiba,Toshiki Saito, et al.FunctionalDiversity among Notch1, Notch2,and Notch3 Receptors. Bioch-emical and Biophysical Research Communications,2002,291:775-779
53 Paul Beatus, Johan Lundkvist, Camilla Oberg, et al. The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity.Mechanisms of Delopment,2001,104:1-30
2杨秉辉,夏景林.原发性肝癌的临床诊断与分期标准.中华肝脏病杂志, 2001, 9(6): 324
3 Li R,Younes M,Wheeler TM,et al.Expression of vascular endothelial growth factor receptor-3(VEGFR-3)in human prostate.Prostate,2004, 58(2):193-199
4 MC Cantarini,Smdela Monte,MPang,et al.Aspartyl-asparagyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Hepatology,2006,44(2):446-57
5 Roy M,Pear WS,Aster JC.The multifaceted role of Notch incancer. Curr Opin Genet Dev,2007,17(1):52-59
6董学斌,纪春岩,马道新,等.Notch信号在人类乳腺癌的作用.中华肿瘤学杂志, 2007, 29(6): 425-428
7 Tonon G,Modi S,Wu L,et al.t(11;19)(q21;p13) translocation inmucoep- idermoid carcinoma creates a novel fusion productthat disrupts a Notch signaling pathway.Nat Genet,2003,33(2):208-213
8 Nicolas M,Wolfer A,Raj K,et al.Notch1 functions as a tumor suppressor in mouse skin.Nat Genet,2003,33(33):416-421
9 Sriuranpong V,Borges MW,Ravi RK,et al.Notch signaling induces cell cycle arrest in small cell lung cancer cells.Cancer Res,2001,61(7): 3200-3205
10 Kerbel RS.Tumor angiogenesis: past,present and the near future. Carcinogenesis,2000, 21(3):505-515
11 Zagouras P,Stifani S,Blaumueller CM,et al.Alterations in Notchsignalingin neoplastic lesions of the human cervix. Proc Natl Acad Sci USA,1995, 92(14):6414-6418
12 Qi R,An H,Yu Y,et al.Notch1 signaling inhibits growth of human hepatocellular carcinoma through induction of cell cycle arrest and apoptosis.Cancer Res,2003,63(23): 8323 -8329
13 MC Cantarini,SM dela Monte,M Pang,etal.Aspartyl-aspa-ragyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms. Hepatology,2006,44(2):446-57
14 Nijjar SS,Crosby HA,Wallace L,et al.Notch receptor expression in adult human liver:apossible role in bile duct forma-tion and hepatic neovascularization.Hepatology,2001,34(6):118421192
15 Nijjar SS,Wallace L,Crosby HA,et al.Altered Notch ligand expression in human liver disease[J]. Am J of pathol,2002,160(5):1695-1703
16 Gramantieri L, Giovannini C, Lanzi A,et al.Aberrant Notch 3 and Notch4 expression in human hepatocellular carcinoma. Liver Int, 2007, 27(7): 997-1007
17杨志云,姚树坤,殷飞,等.清肝化瘀方对大鼠肝癌前病变模型Notch信号系统的影响.中医杂志,2006, 47(12):933-935
18徐洪雨,李宝杰,王瑞峰,等.Notch/Jagged信号在肝部分切除后肝再生中的表达.胃肠病学和肝病学杂志,2007,16(5):465-467
19 Gao J, Song Z, Chen Y,et al.Deregulated expression of No-receptors in human hepatocellular carcinoma [J]. Dig LiverDis,2008, 40(2): 114-121
20 Gao J, Chen C, HongL,etal.Expression ofJagged1 and itsassociationwith hepatitisB virusX protein in hepatocellular carcinoma.Biochem Biophys Res Commun, 2007, 356(2): 341-347.
21 Cantarini MC,Monte SM,Pang M,et al.Aspartly-aspa-ragyl beta hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and not-ch signaling mechanisms.Hepatology,2006,44(2):446-457
22 Chunmei Wang, Runzi Qi, Nan Li, et al. Notch1 Signaling Sensitizes Tumor Necrosis Factor-related Apoptosis-indu-ing Ligand-induced Apoptosis in Human Hepatocellular Carcinoma Cells by Inhibiting Akt/Hdm2-mediated p53 DDegradation and Up-regulating p53-dependent DR5 Expr-ession. Biological ehemistry,2009,284(24): 16183-16190
23 Miki A,Yano Y, KatoH,et al.Anti-tumor effect of pegylatedinterferon in the rat hepato carcinogenesis model. Int J Onco,2008, 32(3): 603-608
24 Kohler C, Bell AW, Bowen WC, et al. Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration. Hepatology, 2004,39(4):1056-65
25肖迎,王琪,鲁凤菊,等. Notch1蛋白在胚胎干细胞向神经细胞诱导分化过程中的表达及意义.山东医药,2007, 47(20):20-22
26徐洪雨,王瑞峰,李宝杰.Notch-1蛋白在诱导骨髓间充质干细胞向肝细胞分化中的表达.哈尔滨医科大学学报,2009,43(2):122-125
27 Kumano K,Chiba S,Shimizu K,et al.Notch1 inhibits diff-rentiation of hematopotetic cells by sustaining GATA-2 expression.Blood, 2001, 98:3283-3289
28 Zhang S,Balch C,Chan MW,et al.Identification and charac-terization of ovarian cancer–initiating cells from primary human tumors[J].Cancer Res,2008,68(11)43111-4320
29 Ma S,Chan KW,Hu L,et al.Identification and characteriza-tion of tumor genic liver cancer stem/progenitor cell[J].Gastroenterology, 2007,132(7): 2542-2556
30 Fan X,Matsui W,Khaki L,et al.Notch pathway inhibition Depletes stem-like cells and blocks engraftment in embryonal brain tumors.Cancer Res,2006,66(15):7445-7552
31龚加庆,方驰华,李雅.卵圆细胞参与实验性肝癌形成过程的研究.中华外科杂志,2004,42:291-295
32 Lowels,Kll,Bernnan BA,et al.Oval cell numbers in human chronic liver diseases are directly related to disease severity.Am J Pathol,1999, 154:537-541
33 Chi-hua Fnag,Wei-Zhang Xin,Yong Zhu, et al.The expression of c-kit and prolieferation cell nuclear antigen in oval cells of mice with hepa-tocellular carcimoma. Hepatobiliary Panceratic Dis Int.2003,2:481-487
34杨志云,姚树坤,殷飞,等.清肝化瘀方对大鼠肝癌前病变模型Notch信号系统的影响.中医杂志,2006, 47(12):933-935
35 Jesen CH,Jauho EI,Santoni–Rugiu E,et al.Transit-amplifying duct-ular (oval)cell and their hepatocytic progeny are characterized by a noval and distinctive expression of delta-like protein/preadipocyte factor I/fetel antigen.Am J Pathol,2004,164(4):1347-1359
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52 Kiyoshi Shimizu,Shigeru Chiba,Toshiki Saito, et al.FunctionalDiversity among Notch1, Notch2,and Notch3 Receptors. Bioch-emical and Biophysical Research Communications,2002,291:775-779
53 Paul Beatus, Johan Lundkvist, Camilla Oberg, et al. The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity.Mechanisms of Delopment,2001,104:1-30