Nup107和claudin23在转移性胰腺癌中的作用及分子机制的初步研究
|
摘要
前言
胰腺癌是一种恶性程度极高的肿瘤,一个重要原因是胰腺癌具有的高度侵袭转移特性。在前期研究中,利用仓鼠实验性胰腺癌模型建立了两种转移能力完全不同的细胞株,解离型高转移(PC-1.0)和非解离型低转移(PC-1)胰腺癌细胞。在前期研究中,我们通过cDNA微阵列分析(cDNA microarray analysis),发现核孔蛋白107(nucleoporin 107kDa, Nup107)及紧密连接蛋白claudin23是解离型高转移株PC-1.0细胞与非解离型低转移株PC-1细胞中的差异表达基因。
核孔复合体(Nuclear pore complexes, NPC)是近年来发现的贯穿于核膜作为细胞核与细胞质物质交换的惟一通道,在细胞正常的生长与分化中发挥着重要作用。研究已发现核孔蛋白结构与功能的改变与疾病及肿瘤发生、发展的关系密切。Nup107是核孔复合体中的一员,是NPC结构的重要核孔蛋白。有文献报道脑恶性胶质瘤细胞中Nup107表达显著增多,但Nup107在胰腺癌中作用尚无报道,其在肿瘤细胞中的作用机制也不清楚。claudin蛋白是构成细胞膜紧密连接至关重要的成分,claudin属于一个多基因家族,到目前为止,已有24种claudin成员被发现,其遗传表达的变化可导致上皮细胞、内皮细胞结构破坏、功能受损,与多种疾病的发生、发展存在密切关系,现已证实claudin家族蛋白成员在肿瘤发生、发展,肿瘤侵袭转移中具有重要作用。有文献报道claudin23在肠型胃癌中下调,但其在胰腺癌中作用尚无报道,其在肿瘤细胞中的作用机制不清楚。
前期研究表明促丝裂原活化蛋白激酶(MAPK)信号转导通路的活化密切参与胰腺发生发展过程的调控,其具体分支通路定位于表皮生长因子受体(EGFR)／丝裂原活化蛋白激酶激酶(MEK)／细胞外信号调节激酶(ERK)。但胰腺癌中Nup107及claudin23的表达与MAPK信号转导通路的关系尚不明确。
本研究中利用免疫细胞化学和RNA干扰的等技术,探讨究Nup107及claudin23在胰腺癌细胞株中的作用及相关作用机制。初步探讨Nup107及claudin23在胰腺癌发生及进展中的作用。
目的
初步探讨Nup107及claudin23在胰腺癌进展中作用的分子机制。同时为开发新型抗胰腺癌侵袭转移的高效治疗方法提供具有重要参考价值的新靶标。
方法
1.用RT-PCR、Western-blot方法验证Nup107 mRNA在解离型高转移株PC-1.0细胞与非解离型低转移株PC-1细胞中表达存在差异。
2.用脂质体转染法将Nup107 siRNA转染入解离型高转移株PC-1.0胰腺癌细胞。用RT-PCR和Western-blot观察转染48h后PC-1.0胰腺癌细胞中Nup107mRNA、蛋白的表达以及MEK mRNA、蛋白的表达变化；应用流式细胞技术及CCK-8法分别检测转染后PC-1.0胰腺癌细胞细胞周期及增殖的变化情况；Papanicolaou'S染色法观察细胞解离状态及Transwell小室结合Matrix胶检测侵袭能力的变化。
3.用稳定转染MEK1-shRNA和MEK2-shRNA的PC-1.0细胞检测Nup107 mRNA及蛋白表达的变化。
4.用RT-PCR、Western-blot及免疫细胞化学方法研claudin23的表达及定位变化与胰腺癌细胞解离的关系。
结果
解离型高转移株PC-1.0细胞中Nup107 mRNA及蛋白表达高于非解离型低转移株PC-1细胞中表达；转染Nup107 siRNA 48h组与各对照组细胞相比,Nup107的mRNA、蛋白的表达明显减少(P<0.01),PC-1.0细胞在转染48h后细胞Gl期比例增加,S期、G2期细胞减少,细胞增殖受到抑制；细胞解离受到抑制,侵袭能力降低。稳定转染MEK1-shRNA和MEK2-shRNA的PC-1.0细胞与PC-1.0细胞相比,在MEK1-shRNA细胞中nup107 mRNA及蛋白表达减少明显,而在MEK2-shRNA细胞中减少不明显。claudin23 mRNA及蛋白在解离型高转移株PC-1.0细胞中低表达,而非解离型低转移株PC-1细胞中高表达,MEK1-shRNA的PC-1.0细胞中claudin23 mRNA及蛋白表达增加,而在MEK2-shRNA细胞中变化不明显。而PC-1+DF处理后,claudin23表达明显减少(P<0.05)并破坏claudin23在细胞膜的定位,细胞开始解离。
结论
1.Nup107参与胰腺癌细胞解离状态、增殖、细胞周期及体外侵袭的调控。
2.Nup107参与胰腺癌的发展过程,其具体的机制可能为主要通过MEK1信号转导通路调控胰腺癌的增殖及细胞周期的变化,并通过MEK2信号通路调控胰腺癌的癌细胞解离状态及侵袭能力。
3. MEK1/2信号转导通路通过调控Nup107的表达,来影响胰腺癌细胞解离状态、增殖、细胞周期及侵袭能力。
4.claudin23表达及定位与胰腺癌细胞解离状态密切相关,其可能的分子机制为,激活了MEK2信号通路。
Pancreatic cancer is known to be an extremely lethal neoplasm, one of the reasons being that pancreatic cancer itself has an extremely high potential of invasion-metastasis. In our previous study, two pancreatic cancer cell lines with a different potential for invasion-metastasis, PC-1 with a low potential and PC-1.0 with a high potential of invasion-metastasis after intrapancreatic transplantation, were established in a Syrian golden hamster. In our previous study, Differential expression of candidate genes Nup107 and claudin23 were indentified by cDNA microarray analysis.
The nuclear pore complex (NPC) is a massive,multiprotin structure responsible for traffic between the nucleus and cytoplasm, it plays a critical role,not only in cell survival,but also in other cellular events such as differentiation. It's structure and function change is correlated to tumorigenesis and development. Nup107 is a component of the nuclear pore complex, a important nucleoporin.In the current study,the expression of Nup107 were increased in spongiocytoma cell.But it has no report about pancreatic cancer, and the mechanism remains incompletely understood.
claudins are essential component of the intercellular tight junction, its are multigene family. Today, the claudin superfamily consists of 24 members in eukaryotes. the genetic expression change of claudin may induce endothelial cell and epithelial cell breakdown,and they are involved in many disease. The claudin family member may play an important role in tumorigenesis and development,also in invasion and metastasis. In the current study,the expression of claudin23 were decreased in intestinal type gastric cancer cell. But it has no report about signal transduction pathway, and the mechanism remains incompletely understood.
In our previous study, the mitogen-activated protein kinase (MAPK) signal transduction pathway y plays a central role in pancreatic cancer progression. The special pathway align on epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). But the relationship between Nup107 or claudin23 and MAPK signal transduction pathway in pancreatic cancer is still unclear.
In this study,intends to claudin23 by immunoocytochemistry and Nup107 through the expression of RNAi technology in the pancreatic cancer cell lines Preliminary study Nup107 and claudin23 in the pathogenesis of pancreatic cancer in the role in order to investigate the occurrence and development of pancreatic cancer relationship
Objective
To study the role of Nup107 and claudin23 in the pathogenesis of pancreatic cancer and molecule mechanisms; To provide a new targer to bring a new method of gene therapy for pancreatic cancer.
Methods
Using RT-PCR and Western-blot observed the mRNA and protein expression of Nup107 in PC-1 with a low potential and PC-1.0 with a high potential of invasion-metastasis. With Lipofectamine method Nup107 siRNA transfected into pancreatic cancer cells. Using RT-PCR and Western-blot observed the mRNA and protein expression of Nup107 and MEK in the PC-1.0 cells after transfection 48h and the flow cytometry, CCK-8, Papanicolaou'staining and a Matrix gel coated Tanswell plate were used separately to detect the cell cycle, changes in proliferation,cell dissociation and invasion ability. Using RT-PCR and Western-blot observed the mRNA and protein expression of Nup107 in the stable transfection MEKl-shRNA and MEK2-shRNA PC-1.0 cells. Using RT-PCR, Western-blot and immunoocytochemistry observed the mRNA and protein expression and distribution of claudin 23
Results
The mRNA and protein expression of Nup107 in PC-1.0 with a high potential of invasion-metastasis are higher than PC-1 with a low potential.Nup107 siRNA transfection group compared with the control group cells, Nup107's mRNA, protein expression was significantly reduced (P<0.01). cells'proliferation was inhibited after transfection transfected,cells increased the proportion of G1 phase, S phase、G2 phase cells decreased and cell dissociation and invasion ability were also restrained. Nup107's mRNA and protein expression was significantly reduced (P<0.01) in the stable transfection MEKl-shRNA PC-1.0 cells, but MEK2-shRNA PC-1.0 cells have no significant changes (P>0.05). The mRNA and protein expression of claudin23 in PC-1.0 with a high potential of invasion-metastasis are lower than PC-1 with a low potential (P<0.05). After incubation with dissocation factor conditioned medium(DF-CM) of PC-1.0 cells, plasma membrane distribution of claudin23 was obviously disrupted, and expressions of claudin23 decreased in PC-1 cells. claudin23 's mRNA and protein expression was significantly increased (P<0.05) in the stable transfection MEK1-shRNA PC-1.0 cells, but MEK2-shRNA PC-1.0 cells have no significant changes (P>0.05).
Conclusions
Nup107 has a key role of cell cycle, cell proliferation,cell dissociation and invasion ability in pancreatic cancer. Nup107 has important effect in the occurrence and development of pancreatic cancer cells. The effect of cell cycle and cell proliferation were through the cellular transduction MAPK/MEK1 pathway, The effect of cell dissociation and invasion ability were through the cellular transduction MAPK/MEK2 pathway. The effect of cell cycle, cell proliferation,cell dissociation and invasion ability were regulated the expression of Nup107 through the cellular transduction MAPK/MEK1/2 pathway. Arragement of expression and distribution of claudin23 is closely related to cell dissocation status in pancreatic cancer cell through MEK2 activation.
胰腺癌是一种恶性程度极高的肿瘤,一个重要原因是胰腺癌具有的高度侵袭转移特性。在前期研究中,利用仓鼠实验性胰腺癌模型建立了两种转移能力完全不同的细胞株,解离型高转移(PC-1.0)和非解离型低转移(PC-1)胰腺癌细胞。在前期研究中,我们通过cDNA微阵列分析(cDNA microarray analysis),发现核孔蛋白107(nucleoporin 107kDa, Nup107)及紧密连接蛋白claudin23是解离型高转移株PC-1.0细胞与非解离型低转移株PC-1细胞中的差异表达基因。
核孔复合体(Nuclear pore complexes, NPC)是近年来发现的贯穿于核膜作为细胞核与细胞质物质交换的惟一通道,在细胞正常的生长与分化中发挥着重要作用。研究已发现核孔蛋白结构与功能的改变与疾病及肿瘤发生、发展的关系密切。Nup107是核孔复合体中的一员,是NPC结构的重要核孔蛋白。有文献报道脑恶性胶质瘤细胞中Nup107表达显著增多,但Nup107在胰腺癌中作用尚无报道,其在肿瘤细胞中的作用机制也不清楚。claudin蛋白是构成细胞膜紧密连接至关重要的成分,claudin属于一个多基因家族,到目前为止,已有24种claudin成员被发现,其遗传表达的变化可导致上皮细胞、内皮细胞结构破坏、功能受损,与多种疾病的发生、发展存在密切关系,现已证实claudin家族蛋白成员在肿瘤发生、发展,肿瘤侵袭转移中具有重要作用。有文献报道claudin23在肠型胃癌中下调,但其在胰腺癌中作用尚无报道,其在肿瘤细胞中的作用机制不清楚。
前期研究表明促丝裂原活化蛋白激酶(MAPK)信号转导通路的活化密切参与胰腺发生发展过程的调控,其具体分支通路定位于表皮生长因子受体(EGFR)／丝裂原活化蛋白激酶激酶(MEK)／细胞外信号调节激酶(ERK)。但胰腺癌中Nup107及claudin23的表达与MAPK信号转导通路的关系尚不明确。
本研究中利用免疫细胞化学和RNA干扰的等技术,探讨究Nup107及claudin23在胰腺癌细胞株中的作用及相关作用机制。初步探讨Nup107及claudin23在胰腺癌发生及进展中的作用。
目的
初步探讨Nup107及claudin23在胰腺癌进展中作用的分子机制。同时为开发新型抗胰腺癌侵袭转移的高效治疗方法提供具有重要参考价值的新靶标。
方法
1.用RT-PCR、Western-blot方法验证Nup107 mRNA在解离型高转移株PC-1.0细胞与非解离型低转移株PC-1细胞中表达存在差异。
2.用脂质体转染法将Nup107 siRNA转染入解离型高转移株PC-1.0胰腺癌细胞。用RT-PCR和Western-blot观察转染48h后PC-1.0胰腺癌细胞中Nup107mRNA、蛋白的表达以及MEK mRNA、蛋白的表达变化；应用流式细胞技术及CCK-8法分别检测转染后PC-1.0胰腺癌细胞细胞周期及增殖的变化情况；Papanicolaou'S染色法观察细胞解离状态及Transwell小室结合Matrix胶检测侵袭能力的变化。
3.用稳定转染MEK1-shRNA和MEK2-shRNA的PC-1.0细胞检测Nup107 mRNA及蛋白表达的变化。
4.用RT-PCR、Western-blot及免疫细胞化学方法研claudin23的表达及定位变化与胰腺癌细胞解离的关系。
结果
解离型高转移株PC-1.0细胞中Nup107 mRNA及蛋白表达高于非解离型低转移株PC-1细胞中表达；转染Nup107 siRNA 48h组与各对照组细胞相比,Nup107的mRNA、蛋白的表达明显减少(P<0.01),PC-1.0细胞在转染48h后细胞Gl期比例增加,S期、G2期细胞减少,细胞增殖受到抑制；细胞解离受到抑制,侵袭能力降低。稳定转染MEK1-shRNA和MEK2-shRNA的PC-1.0细胞与PC-1.0细胞相比,在MEK1-shRNA细胞中nup107 mRNA及蛋白表达减少明显,而在MEK2-shRNA细胞中减少不明显。claudin23 mRNA及蛋白在解离型高转移株PC-1.0细胞中低表达,而非解离型低转移株PC-1细胞中高表达,MEK1-shRNA的PC-1.0细胞中claudin23 mRNA及蛋白表达增加,而在MEK2-shRNA细胞中变化不明显。而PC-1+DF处理后,claudin23表达明显减少(P<0.05)并破坏claudin23在细胞膜的定位,细胞开始解离。
结论
1.Nup107参与胰腺癌细胞解离状态、增殖、细胞周期及体外侵袭的调控。
2.Nup107参与胰腺癌的发展过程,其具体的机制可能为主要通过MEK1信号转导通路调控胰腺癌的增殖及细胞周期的变化,并通过MEK2信号通路调控胰腺癌的癌细胞解离状态及侵袭能力。
3. MEK1/2信号转导通路通过调控Nup107的表达,来影响胰腺癌细胞解离状态、增殖、细胞周期及侵袭能力。
4.claudin23表达及定位与胰腺癌细胞解离状态密切相关,其可能的分子机制为,激活了MEK2信号通路。
Pancreatic cancer is known to be an extremely lethal neoplasm, one of the reasons being that pancreatic cancer itself has an extremely high potential of invasion-metastasis. In our previous study, two pancreatic cancer cell lines with a different potential for invasion-metastasis, PC-1 with a low potential and PC-1.0 with a high potential of invasion-metastasis after intrapancreatic transplantation, were established in a Syrian golden hamster. In our previous study, Differential expression of candidate genes Nup107 and claudin23 were indentified by cDNA microarray analysis.
The nuclear pore complex (NPC) is a massive,multiprotin structure responsible for traffic between the nucleus and cytoplasm, it plays a critical role,not only in cell survival,but also in other cellular events such as differentiation. It's structure and function change is correlated to tumorigenesis and development. Nup107 is a component of the nuclear pore complex, a important nucleoporin.In the current study,the expression of Nup107 were increased in spongiocytoma cell.But it has no report about pancreatic cancer, and the mechanism remains incompletely understood.
claudins are essential component of the intercellular tight junction, its are multigene family. Today, the claudin superfamily consists of 24 members in eukaryotes. the genetic expression change of claudin may induce endothelial cell and epithelial cell breakdown,and they are involved in many disease. The claudin family member may play an important role in tumorigenesis and development,also in invasion and metastasis. In the current study,the expression of claudin23 were decreased in intestinal type gastric cancer cell. But it has no report about signal transduction pathway, and the mechanism remains incompletely understood.
In our previous study, the mitogen-activated protein kinase (MAPK) signal transduction pathway y plays a central role in pancreatic cancer progression. The special pathway align on epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK). But the relationship between Nup107 or claudin23 and MAPK signal transduction pathway in pancreatic cancer is still unclear.
In this study,intends to claudin23 by immunoocytochemistry and Nup107 through the expression of RNAi technology in the pancreatic cancer cell lines Preliminary study Nup107 and claudin23 in the pathogenesis of pancreatic cancer in the role in order to investigate the occurrence and development of pancreatic cancer relationship
Objective
To study the role of Nup107 and claudin23 in the pathogenesis of pancreatic cancer and molecule mechanisms; To provide a new targer to bring a new method of gene therapy for pancreatic cancer.
Methods
Using RT-PCR and Western-blot observed the mRNA and protein expression of Nup107 in PC-1 with a low potential and PC-1.0 with a high potential of invasion-metastasis. With Lipofectamine method Nup107 siRNA transfected into pancreatic cancer cells. Using RT-PCR and Western-blot observed the mRNA and protein expression of Nup107 and MEK in the PC-1.0 cells after transfection 48h and the flow cytometry, CCK-8, Papanicolaou'staining and a Matrix gel coated Tanswell plate were used separately to detect the cell cycle, changes in proliferation,cell dissociation and invasion ability. Using RT-PCR and Western-blot observed the mRNA and protein expression of Nup107 in the stable transfection MEKl-shRNA and MEK2-shRNA PC-1.0 cells. Using RT-PCR, Western-blot and immunoocytochemistry observed the mRNA and protein expression and distribution of claudin 23
Results
The mRNA and protein expression of Nup107 in PC-1.0 with a high potential of invasion-metastasis are higher than PC-1 with a low potential.Nup107 siRNA transfection group compared with the control group cells, Nup107's mRNA, protein expression was significantly reduced (P<0.01). cells'proliferation was inhibited after transfection transfected,cells increased the proportion of G1 phase, S phase、G2 phase cells decreased and cell dissociation and invasion ability were also restrained. Nup107's mRNA and protein expression was significantly reduced (P<0.01) in the stable transfection MEKl-shRNA PC-1.0 cells, but MEK2-shRNA PC-1.0 cells have no significant changes (P>0.05). The mRNA and protein expression of claudin23 in PC-1.0 with a high potential of invasion-metastasis are lower than PC-1 with a low potential (P<0.05). After incubation with dissocation factor conditioned medium(DF-CM) of PC-1.0 cells, plasma membrane distribution of claudin23 was obviously disrupted, and expressions of claudin23 decreased in PC-1 cells. claudin23 's mRNA and protein expression was significantly increased (P<0.05) in the stable transfection MEK1-shRNA PC-1.0 cells, but MEK2-shRNA PC-1.0 cells have no significant changes (P>0.05).
Conclusions
Nup107 has a key role of cell cycle, cell proliferation,cell dissociation and invasion ability in pancreatic cancer. Nup107 has important effect in the occurrence and development of pancreatic cancer cells. The effect of cell cycle and cell proliferation were through the cellular transduction MAPK/MEK1 pathway, The effect of cell dissociation and invasion ability were through the cellular transduction MAPK/MEK2 pathway. The effect of cell cycle, cell proliferation,cell dissociation and invasion ability were regulated the expression of Nup107 through the cellular transduction MAPK/MEK1/2 pathway. Arragement of expression and distribution of claudin23 is closely related to cell dissocation status in pancreatic cancer cell through MEK2 activation.
引文
1 Tan X, Egami H, Ishikawa S, et al. Arrangement of expression and distribution of tight junction protein claudin23 in cell dissociation of pancreatic cancer cells. Int J Oncol. 2004;25:1567-1574.
2 Tan X, Egami H, Ishikawa S, et al. Relationship between activation of epidermal growth factor receptor and cell dissociation in pancreatic cancer. Int J Oncol.2004;25:1303-1309.
3 Tan X, Tamori Y, Egami H, et al. Analysis of invasion-metastasis mechanism in pancreatic cancer:Involvement of tight junction transmembrane protein occludin and MEK/ERK signal transduction pathway in cancer cell dissociation. Oncol Rep.2004; 11.993-998.
4 Tan X, Zhou L, Wang W, et al. Genomic analysis of invasion-metastasis related factors in pancreatic cancer cells. Exp Ther Med.2010; 1:211-216.
5 D'angelo Ma, Hetzer MW. Structure, dynamics and function of nuclear pore complexes. Trends Cell Biol.2008; 18:456-466
6 Fahrenkrog B, Koser J, aebi u. the nuclear pore complex:a jack of all trades? Trends Biochem Sci.2004;29:175-182
7 Zhang X, Chen S, Yoo S, Chakrabarti S, et al. Mutation in nuclear pore component nup155 leads to atrial fibrillation and early sudden cardiac death. Cell.2008;135:1017-1027
8 Grimaldi Mr, cozzolino l, Malva graziani F, et al. nup154 genetically interacts with cup and plays a cell-type-specific function during Drosophila melanogaster egg-chamber development. Genetics.2007; 175:1751-1759
9 Wesierska-gadek J, Klima Komina o, ranftler c, et al. characterization of autoantibodies against components of the nuclear pore complexes:high frequency of anti-p62 nucleoporin antibodies. Ann NY Acad Sci.2007; 1109:519-530
10 Basel-Vanagaite, et al. Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann Neurol.2006;60:214-222
11 Neilson DE, Adams MD, Orr CM, et al. infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, ranBp2. Am J Hum Genet.2009; 84:44-51
12 Lupu F, alves a, anderson K, et al. nuclear pore composition regulates neural stem/progenitor cell differentiation in the mouse embryo. Dev Cell.2008; 14:831-842
13 Graux, et al. Fusion of nup214 to aBll on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet.2004;36:1084-1089
14 Saito S, Miyaji-yamaguchi M, nagata K. aberrant intracellular localization of SEt-can fusion protein, associated with a leukemia, disorganizes nuclear export. Int J Cancer.2004;111: 501-507
15 Uv aE, roth p, Xylourgidis n, et al. members only encodes a Drosophila nucleoporin required for rel protein import and immune response activation. Genes Dev.2000;14:1945-1957
16 Martinez, N, Alonso A, Moragues MD, et al. The nuclear pore complex protein Nup88 is overexpressed in tumor cells. Cancer Res.1999;59:5408-5411
1717. Gould, V.E, Orucevic A, Zentgraf H, et al. Nup88 (karyoporin) in human malignant neoplasms and dysplasias:correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis. Hum. Pathol.2002;33:536-544
18 Emterling, A, Skoglund J, Arbman G, et al. Clinicopathological significance of Nup88 expression in patients with colorectal cancer. Oncology.2003;64:361-369
19 Agudo D, Gomez-Esquer F, Martinez-Arribas F, et al. Nup88 mRNA overexpression is associated with high aggressiveness of breast cancer. Int. J. Cancer.2004; 109:717-720
20 Gould VE, Martinez N, Orucevic A, et al. A novel, nuclear pore-associated, widely distributed molecule overexpressed in oncogenesis and development. Am J Pathol 2000;157:1605-1613.
21 Knoess M, Kurz AK, Goreva O, et al. Nucleoporin 88 expression in hepatitis B and C virus-related liver diseases.World J Gastroenterol.2006; 12:5870-5874.
22 Zhang ZY, Zhao ZR, Jiang L, et al.Nup88 expression in normal mucosa, adenoma, primary adenocarcinoma and lymph node metastasis in the colorectum. Tumour Biol 2007;28:93-99
23 Wu X, Kasper LH, Mantcheva RT, et al. Disruption of the FG nucleoporin NUP98 causes selective changes in nuclear pore complex stoichiometry and function. Proc Natl Acad Sci USA 2001;98:3191-3196.
24 Borrow J, Shearman AM, Stanton VP, et al.The t(7; 11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin Nup98 and class 1 homeoprotein HoxA9. Nat Genet 1996;12:159-167.
25 Fujino T, Suzuki A, Ito Y, et al.Singletranslocation and double-chimeric transcripts:detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(pl5;p15). Blood 2002;99:1428-1433.
26 Suzuki A, Ito Y, Sashida G, et al. t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion. Br J Haematol 2002;116:170-172.
27 Taketani T, Taki T, Shibuya N, et al. The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Cancer Res 2002;62:33-37.
28 Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, et al.NUP98-HOXD13 gene fusion in therapy-related acutemyelogenous leukemia. Cancer Res 1998;58:4269-4273.
29 Alber F, Dokudovskaya S, Veenhoff LM, et al. molecular architecture of the nuclear pore complex. Nature.2007;450:695-701
30 Hodgson JG, Yeh RF, Ray A, Wang NJ, et al. Comparative analyses of gene copy number and mRNA expression in GBM tumors and GBM xenografts. Neuro Oncol.2009 Oct; 11:477-487.
31 Constanze Will,1,2 Michael Fromm,3 and Dominik Mullerl,2. Claudin tight junction proteins:novel aspects in paracellular transport. Peritoneal Dialysis International.2008; 28: 577-584
32 Woods DF and Bryant PJ. Molecular cloning of the lethal (1)discs large-1 oncogene of Drosophila[J].Dev Biol.1989;134:222-235.
33 Soler AP,Miller RD,Laughlin KV Carp NZ Klurfeld DM and Mullin JM.Increased tight junctional permeabilityis associated with the development of colon cancer [J].Carcinogenesis.1999;20:1425-1432.
34 Kleeff J, Shi X,Bode HP, et al. Altered expression and localization of the tight junction protein ZO-1 in primary and metasasis pancreatic cancer [J]. Pancreas.2001;23:259-265.
35 Katoh M, Katoh M. claudin23 gene, frequently down-regulated in intestinal-type gastric cancer, is a novel member of CLAUDIN gene family. Int J Mol Med.2003; 11:683-689
36 Egami H, Takiyama Y, Cano M, et al. Establishment of hamster pancreatic ductal carcinoma cell line (PC-1) producing blood group-related antigens. Carcinogenesis.1989;10:861-869.
37 Egami H, Tomioka T, Tempero M, et al. Development of intrapancreatic transplantable model of pancreatic duct adenocarcinoma in syrian golden hamsters. Am J Pathol.1991; 138: 557-561.
38 Pour PM, Egami H, Takiyama Y. Patterns of growth and metastases of induced pancreatic cancer in relation to the prognosis and its clinical implications. Gastroenterology.1991; 100: 529-536.
39 Kurizaki T, Egami H, Hirota M, et al. Characterization of cancer cell dissociation factor in a highly invasive pancreatic cancer cell line. Cancer.1995 75:1554-1561.
40 Hinshaw JE, Carragher BO, Milligan RA, et al. Architecture and design of the nuclear pore complex. Cell.1992; 69:1133-1141
41 Akey, C.W. and Radermacher, M. Architecture of the Xenopus nuclear pore complex revealed by three-dimensional cryo-electron microscopy. J. Cell Biol.1993; 122:1-19
42 Stoffler, D, Feja B, Fahrenkrog B, et al. Cryo-electron tomography provides novel insights into nuclear pore architecture:implications for nucleocytoplasmic transport. J. Mol. Biol. 2003;328:119-130
43 Yang Q, Rout MP, Akey CW. Three-dimensional architecture of the isolated yeast nuclear pore complex:functional and evolutionary implications. Mol. Cell.1998;223-234
44 Birthe Fahrenkrog, Joachim Koser and Ueli Aebi.he nuclear pore complex:a jack of all trades? TRENDS in Biochemical Sciences.2004;29:175-182
45 D'angelo Ma, Hetzer MW. Structure, dynamics and function of nuclear pore complexes. Trends Cell Biol.2008; 18:456-466
46 Weis K. nuclear pore complex:oily spaghetti or gummy bear? Cell.2007; 130:405-407
47 Cronshaw JM, Krutchinsky an, zhang W, et al. Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol.2002; 158:915-927
48 Mythili Suntharalingaml, and Susan R Wente.Peering through the pore:nuclear pore complex structure, assembly, and function. Dev Cell.2003;4:775-789.
49 Kurt E. Gustin.hibition of nucleo-cytoplasmic trafficking by RNA viruses:targeting the nuclear pore complex. Virus Res.2003;95:35-44.
50 Gustin KE, Sarnow P.Effects of poliovirus infection on nucleo-cytoplasmic trafficking and nuclear pore complex composition. EMBO J.2001; 20:240-249.
51 Ball JR, Ullman KS.Versatility at the nuclear pore complex:lessons learned from the nucleoporin Nup153. Chromosoma.2005;114:319-330
52 Meier i, Brkljacic J. the nuclear pore and plant development. Curr Opin Plant Biol.2009; 12: 87-95
53 akhtar a, gasser SM. the nuclear envelope and transcriptional control. Nat Rev Genet.2007; 8: 507-517,
54 Brown cr, Kennedy cJ, Delmar Va, Forbes DJ, Silver pa. global histone acetylation induces functional genomic reorganization at mammalian nuclear pore complexes. Genes Dev.2008;22: 627-639
55 Schuldt A. Nuclear pore assembly:locating the linchpin. Nat Cell Biol.2003; 5:497-501.
56 Harel A, Orjalo AV, Vincent T, et al. Removal of a Single Pore Subcomplex Results in Vertebrate Nuclei Devoid of Nuclear Pores. Molecular Cell.2003; 11:853-864.
57 Antonin, W., Franz, C., Haselmann, U., et al. The integral membrane nucleoporin poml21 functionally links nuclear pore complex assembly and nuclear envelope formation. Mol. Cell. 2005;17,83-92.
58 D Angelo, M.A., Anderson, D.J., et al. Nuclear pores form de novo from both sides of the nuclear envelope. Science.2006;312,440-443.
59 Maul GG.uclear pore complexes. Elimination and reconstruction during mitosis. J Cell Biol. 1977;74:492-500.
60 Walther TC, Alves A, Pickersgill H, Loiodice I, Hetzer M. The conserved Nup107-160 complex is critical for nuclear pore complex assembly.Cell.2003;113:195-206.
61 Torimura T, Ueno T, Kin M, et al. Autocrine motility factor enhances hepatoma cell invasion across the basement membrane through activation of β1 integrins. Hepatology.2001;34: 62-71,
62 Fincham VJ, James M, Frame MC, et al. Active ERK/MAP kinase is targeted to newly forming cell-matrix adhesions by integrin engagement and v-Src. EMBO J.2000; 19:2911-2923
63 Rescan C, Coutant A, Talarmin H, et al. Mechanism in the sequential control of cell morphology and S phase entry by epidermal growth factor involves distinct MEK/ERK activations. Mol Biol Cell.2001; 12:725-738
64 Farquhar MG and Palade GE.Junctional complexes in various epithelia[J]. Cell Biol.1963;1 7:375-412.
65 Diamond J.The epithelial junction.bridge,gate,and fence[J]. Physiologist,1997,20:10-18.
66 Lynne AL:The molecular structure of the tight junction[J].Adv Drug Deliv Rev.2000;41:155-164.
67 Sonoda N,Furuse M,Sasaki H, et al.Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands:evidence for direct involvement of claudins in tight junction barrier [J]. Cell Biol.1999;147:195-204.
68 Itoh M, Furuse M, Morita K, et al.Direct binding of three tight junction-associated MAGUKs,ZO-1,ZO-2,ZO-3,with the COOH termni of claudins[J]. Cell Biol 1999;147:1351-1363.
69 Michlig S, Damak S, Coutre JL. Claudin-based permeability barriers in taste buds. J Comp Neurol.2007;502:1003-1011
70 Hirota M, Egami H, Corra S, et al. Production of scatter factor-like activity by a nitrosamine-induced pancreatic cancer cell line. Carcinogenesis.1993; 14:259-264
71 Kurizaki T, Egami H, Hirota M, et al. Characterization of cancer cell dissociation factor in a highly invasive pancreatic cancer cell line. Cancer.1995;75:1554-1561
72 Ishikawa S, Egami H, Kurizaki T, et al. Analysis of the factor related to the signal transduction pathway of invasion and metastasis in pancreatic cancer. J Exp Clin Cancer Res.2003; 22: 299-306
73 Tan X, Egami H, Kamohara H, et al. Involvement of the mitogen-activated protein kinase kinase 2 in the induction of cell dissociation in pancreatic cancer. Int J Oncol.2004; 24:65-73
74 Tan X, Egami H, Ishikawa S, et al:. Relationship between the expression of extracellular signal-regulated kinase 1/2 and the dissociation of pancreatic cancer cells:involvement of ERK1/2 in the dissociation status of cancer cells. Int J Oncol.2004;24:815-820
75 D'Souza T, Agarwal R, Morin PJ. Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent protein kinase regulates tight junction barrier function in ovarian cancer cells. J Biol Chem.2005; 280:26233-26240
76 Stamatovic SM, Dimitrijevic OB, Kepp RF, et al. Protein kinase C a-RhoA cross talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem.2006;281: 8379-8388
77 Yamauchi K, Rai T, Kobayashi K, et al.Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proc Natl Acad Sci U S A.2004; 101: 4690-4694
1 Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in respectable pancreatic cancer:a randomised controlled trial. Lancet 2001; 358:1576-1585
2 DiMagno EP, Reber HA and Tempero MA.AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. Gastroenterolgy 1999; 117:1464-1484
3 Kim J, Yu W, Kovalski K and Ossowski L.Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay. Cell 1998; 94:353-362
4 Hanahan D and Weinberg RA. The hallmarks of cancer. Cell 2000,100:57-70
5 Bishop JM. Molecular themes in oncogenesis. Cell 1991; 64:235-248
6 Cavenee WK, Dryja TP, Phillips RA, et al.Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 1983; 305:779-784
7 Ponder B Cancer. Gene losses in human tumours. Nature 1988; 335:400-402
8 Kinzler KW and Vogelstein B.Life (and death) in a malignant tumour.Nature 1996; 379:19-20
9 Brat DJ, Lillemoe KD, Yeo CJ, et al.Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol 1998; 22:163-169
10 Muller A, Homey B, Soto H, et al.Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410:50-56
11 Borsig L, Wong R, Hynes RO, et al. Synergistic effectsof L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancersof metastasis. Proc Natl Acad Sci U S A 2002;99:2193-2198
12 Tawil NJ, Gowri V, Djoneidi M, et al. Integrin alpha3beta1 can promote adhesion and spreading of metastatic breast carcinoma cells on the lymph node stroma. Int J Cancer 1996; 66:703-710
13 Siesser PF, Maness PF. L1 cell adhesion molecules as regulators of tumor cell invasiveness. Cell Adh Migr.2009; 3:275-277
14 Francavilla C, Maddaluno L, Cavallaro U. The functional role of cell adhesion molecules in tumor angiogenesis. Semin Cancer Biol.2009;19:298-309
15 Hanahan D, Bergers G and Bergsland E.Less is more, regularly:metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000; 105:1045-1047
16 Aplin AE, Howe A, Alahari SK and Juliano RL.Signal transduction and signal modulation by cell adhesion receptors:the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins. Pharmacol Rev 1998; 50:197-263
17 Christofori G and Semb H.The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 1999;24:73-76
18 Karayiannakis AJ, Syrigos KN, Polychronidis A and Simopoulos C.Expression patterns of alpha-, beta- and gamma-catenin in pancreatic cancer:correlation with E-cadherin expression, pathological features and prognosis. Anticancer Res 2001,21:4127-4134
19 Skubitz AP.Adhesion molecules. Cancer Treat Res 2002; 107:305-329
20 Maurer CA, Friess H, Kretschmann B, et al.Over-expression of ICAM-1, VCAM-1 and ELAM-1 might influence tumor progression in colorectal cancer. Int J Cancer 1998; 79:76-81
21 Fogar P, Basso D, Pasquali C, et al. Neural cell adhesion molecule (N-CAM) in gastrointestinal neoplasias. Anticancer Res 1997; 17:1227-1230
22 Tempia-Caliera AA, Horvath LZ, Zimmermann A, et al. Adhesion molecules in human pancreatic cancer. J Surg Oncol 2002; 79:93-100
23 Varner JA and Cheresh DA. Integrins and cancer. Curr Opin Cell Biol 1996; 8:724-730
24 Coussens LM and Werb Z. Matrix metalloproteinases and the development of cancer. Chem Biol 1996; 3:895-904
25 Bloomston M, Zervos EE and Rosemurgy AS.Matrix metalloproteinases and their role in pancreatic cancer:a review of preclinical studies and clinical trials. Ann Surg Oncol 2002; 9:668-674
26 Bergers G, Brekken R, McMahon G, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000; 2:737-744
27 Wang Y.The role and regulation of urokinase-type plasminogen activator receptor gene expression in cancer invasion and metastasis. Med Res Rev 2001; 21:146-170
28 Dano K, Andreasen PA, Grondahl-Hansen J, et al. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 1985; 44:139-266
29 Friess H, Cantero D, Graber H, et al.Enhanced urokinase plasminogen activation in chronic pancreatitis suggests a role in its pathogenesis. Gastroenterology.1997; 113:904-913
30 Bramhall SR, Neoptolemos JP, Stamp GW and Lemoine NR.Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol 1997; 182:347-355
31 Blasi F, Sidenius N. The urokinase receptor:focused cell surface proteolysis, cell adhesion and signaling. FEBS Lett.2010;584:1923-1930.
32 Lamy PJ, Romieu G, Jacot W. UPA/PAI-1:a tool for breast cancer treatment individualization. Biology, clinical implications and quantification assays. Bull Cancer.2010;97:341-348.
33 Cantero D, Friess H, Deflorin J, et al.Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma. Br J Cancer 1997; 75:388-395
34 Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol. 2010;11:23-36.
35 Kleiner DE and Stetler-Stevenson WG.Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol 1999;43(Suppl):S42-S51
36 Yoon SO, Park SJ, Yun CH, et al. Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J Biol Mol Biol.2003;36:128-37.
37 Lohi J, Wilson CL, Roby JD, et al. Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury. J Biol Chem 2001;276:10134-44.
38 38 Cheng K, Xie G, Raufman JP. Matrix metalloproteinase-7-catalyzed release of HB-EGF mediates deoxycholyltaurine-induced proliferation of a human colon cancer cell line. Biochem Pharmacol.2007;73:1001-12
39 Mimori K, Yamashita K, Ohta M, et al. Coexpression of matrix metalloproteinase-7 (MMP-7) and epidermal growth factor (EGF) receptor in colorectal cancer:An EGF receptor tyrosine kinase inhibitor is effective against MMP-7-expressing cancer cells. Clin Cancer Res. 2004; 10:8243-9.
40 Zeng ZS, Shu WP, Cohen AM, et al. Matrix metalloproteinase-7 expression in colorectal cancer liver metastasis:evidence for involvement of MMP-7 activation in human cancer metastasis. Clin Cancer Res.2002;8:144-8.
41 Yamamoto H, Itoh F, Iku S, et al. Expression of matrix metalloproteinases and tissue inhibitors of metatlloproteinases in human pancreatic adenocarcinomas:clinicopathologic and prognostic significance of matrilysin expression. J Clin Oncol.2001; 19:1118-27.
42 Roztocil E, Nicholl SM, Galaria II, et al. Plasmin-induced smooth muscle cell proliferation requires epidermal growth factor activation through an extracellular pathway. Surgery. 2005;138:180-6.
43 Lijnen HR, Collen D. Matrix metalloproteinase system deficiencies and matrix degradation. Thromb Haemost.1999;82:837-45.
44 Yamamoto H, Iku S, Adachi Y, et al. Association of trypsin expression with tumor progression and matrilysin expression in human colorectal cancer. J Pathol.2003; 199:176-84.
45 Moilanen M, Sorsa T, Stenman M, et al. Tumor-associated trypsinogen-2 (trypsinogen-2) activates procollagenases (MMP-1,-8,-13) and stromelysin-1 (MMP-3) and degrades type 1 collag. Biochemistry.2003;42:5414-20.
46 Tan X, Egami H, Abe M, et al. Involvement of matrix metalloproteinase-7 in invasion of pancreatic cancer cells through activation of EGFR-mediated MEK/ERK signal transduction pathway. J Clin Pathol.2005;58:1242-8.
47 Matsuyama Y, Takao S and Aikou T. Comparison of matrix metalloproteinase expression between primary tumors with or without liver metastasis in pancreatic and colorectal carcinomas. J Surg Oncol 2002; 80:105-110
48 Gress TM, Muller-Pillasch F, Lerch MM, et al. Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int J Cancer 1995;62:407-413
49 Joergensen MT, Brunner N, De Muckadell OB. Comparison of circulating MMP-9, TIMP-1 and CA19-9 in the detection of pancreatic cancer. Anticancer Res.2010;30:587-592.
50 Han F, Zhu HG. Caveolin-1 regulating the invasion and expression of matrix metalloproteinase (MMPs) in pancreatic carcinoma cells. J Surg Res.2010;159:443-450
5151. Mroczko B, Lukaszewicz-Zajac M, Wereszczynska-Siemiatkowska U, et al.. Clinical significance of the measurements of serum matrix metalloproteinase-9 and its inhibitor (tissue inhibitor of metalloproteinase-1) in patients with pancreatic cancer:metalloproteinase-9 as an independent prognostic factor. Pancreas.2009;38:613-618.
52 Beatrice S.Knudsen, George Vande Woude.Showering c-MET-dependent cancers with drugs.Current Opinion in Genetics & Development.2008; 18:87-96
53 Paolo M.Comoglio, Livio Trusolino. Invasive growth:from development to metastasis. J Clin Invest.2002; 109:857-862
54 Guo A, Villen J, Kornhauser J, Lee KA, et al. Signaling networks assembled by oncogenic EGFR and c-MET. Proc Natl Acad Sci U S A 2008; 105:692-697.
55 Smallbone K, Gatenby RA, Gillies RJ, et al. Metabolic changes during carcinogenesis: potential impact on invasiveness. J Theor Biol 2007;244:703-713.
56 Osada S, Matsui S, Komori S, et al. Effect of hepatocyte growth factor on progression of liver metastasis in colorectal cancer. Hepatogastroenterology.2010;57:76-80.
2 Tan X, Egami H, Ishikawa S, et al. Relationship between activation of epidermal growth factor receptor and cell dissociation in pancreatic cancer. Int J Oncol.2004;25:1303-1309.
3 Tan X, Tamori Y, Egami H, et al. Analysis of invasion-metastasis mechanism in pancreatic cancer:Involvement of tight junction transmembrane protein occludin and MEK/ERK signal transduction pathway in cancer cell dissociation. Oncol Rep.2004; 11.993-998.
4 Tan X, Zhou L, Wang W, et al. Genomic analysis of invasion-metastasis related factors in pancreatic cancer cells. Exp Ther Med.2010; 1:211-216.
5 D'angelo Ma, Hetzer MW. Structure, dynamics and function of nuclear pore complexes. Trends Cell Biol.2008; 18:456-466
6 Fahrenkrog B, Koser J, aebi u. the nuclear pore complex:a jack of all trades? Trends Biochem Sci.2004;29:175-182
7 Zhang X, Chen S, Yoo S, Chakrabarti S, et al. Mutation in nuclear pore component nup155 leads to atrial fibrillation and early sudden cardiac death. Cell.2008;135:1017-1027
8 Grimaldi Mr, cozzolino l, Malva graziani F, et al. nup154 genetically interacts with cup and plays a cell-type-specific function during Drosophila melanogaster egg-chamber development. Genetics.2007; 175:1751-1759
9 Wesierska-gadek J, Klima Komina o, ranftler c, et al. characterization of autoantibodies against components of the nuclear pore complexes:high frequency of anti-p62 nucleoporin antibodies. Ann NY Acad Sci.2007; 1109:519-530
10 Basel-Vanagaite, et al. Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann Neurol.2006;60:214-222
11 Neilson DE, Adams MD, Orr CM, et al. infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, ranBp2. Am J Hum Genet.2009; 84:44-51
12 Lupu F, alves a, anderson K, et al. nuclear pore composition regulates neural stem/progenitor cell differentiation in the mouse embryo. Dev Cell.2008; 14:831-842
13 Graux, et al. Fusion of nup214 to aBll on amplified episomes in T-cell acute lymphoblastic leukemia. Nat Genet.2004;36:1084-1089
14 Saito S, Miyaji-yamaguchi M, nagata K. aberrant intracellular localization of SEt-can fusion protein, associated with a leukemia, disorganizes nuclear export. Int J Cancer.2004;111: 501-507
15 Uv aE, roth p, Xylourgidis n, et al. members only encodes a Drosophila nucleoporin required for rel protein import and immune response activation. Genes Dev.2000;14:1945-1957
16 Martinez, N, Alonso A, Moragues MD, et al. The nuclear pore complex protein Nup88 is overexpressed in tumor cells. Cancer Res.1999;59:5408-5411
1717. Gould, V.E, Orucevic A, Zentgraf H, et al. Nup88 (karyoporin) in human malignant neoplasms and dysplasias:correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis. Hum. Pathol.2002;33:536-544
18 Emterling, A, Skoglund J, Arbman G, et al. Clinicopathological significance of Nup88 expression in patients with colorectal cancer. Oncology.2003;64:361-369
19 Agudo D, Gomez-Esquer F, Martinez-Arribas F, et al. Nup88 mRNA overexpression is associated with high aggressiveness of breast cancer. Int. J. Cancer.2004; 109:717-720
20 Gould VE, Martinez N, Orucevic A, et al. A novel, nuclear pore-associated, widely distributed molecule overexpressed in oncogenesis and development. Am J Pathol 2000;157:1605-1613.
21 Knoess M, Kurz AK, Goreva O, et al. Nucleoporin 88 expression in hepatitis B and C virus-related liver diseases.World J Gastroenterol.2006; 12:5870-5874.
22 Zhang ZY, Zhao ZR, Jiang L, et al.Nup88 expression in normal mucosa, adenoma, primary adenocarcinoma and lymph node metastasis in the colorectum. Tumour Biol 2007;28:93-99
23 Wu X, Kasper LH, Mantcheva RT, et al. Disruption of the FG nucleoporin NUP98 causes selective changes in nuclear pore complex stoichiometry and function. Proc Natl Acad Sci USA 2001;98:3191-3196.
24 Borrow J, Shearman AM, Stanton VP, et al.The t(7; 11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin Nup98 and class 1 homeoprotein HoxA9. Nat Genet 1996;12:159-167.
25 Fujino T, Suzuki A, Ito Y, et al.Singletranslocation and double-chimeric transcripts:detection of NUP98-HOXA9 in myeloid leukemias with HOXA11 or HOXA13 breaks of the chromosomal translocation t(7;11)(pl5;p15). Blood 2002;99:1428-1433.
26 Suzuki A, Ito Y, Sashida G, et al. t(7;11)(p15;p15) Chronic myeloid leukaemia developed into blastic transformation showing a novel NUP98/HOXA11 fusion. Br J Haematol 2002;116:170-172.
27 Taketani T, Taki T, Shibuya N, et al. The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with t(2;11)(q31;p15). Cancer Res 2002;62:33-37.
28 Raza-Egilmez SZ, Jani-Sait SN, Grossi M, Higgins MJ, et al.NUP98-HOXD13 gene fusion in therapy-related acutemyelogenous leukemia. Cancer Res 1998;58:4269-4273.
29 Alber F, Dokudovskaya S, Veenhoff LM, et al. molecular architecture of the nuclear pore complex. Nature.2007;450:695-701
30 Hodgson JG, Yeh RF, Ray A, Wang NJ, et al. Comparative analyses of gene copy number and mRNA expression in GBM tumors and GBM xenografts. Neuro Oncol.2009 Oct; 11:477-487.
31 Constanze Will,1,2 Michael Fromm,3 and Dominik Mullerl,2. Claudin tight junction proteins:novel aspects in paracellular transport. Peritoneal Dialysis International.2008; 28: 577-584
32 Woods DF and Bryant PJ. Molecular cloning of the lethal (1)discs large-1 oncogene of Drosophila[J].Dev Biol.1989;134:222-235.
33 Soler AP,Miller RD,Laughlin KV Carp NZ Klurfeld DM and Mullin JM.Increased tight junctional permeabilityis associated with the development of colon cancer [J].Carcinogenesis.1999;20:1425-1432.
34 Kleeff J, Shi X,Bode HP, et al. Altered expression and localization of the tight junction protein ZO-1 in primary and metasasis pancreatic cancer [J]. Pancreas.2001;23:259-265.
35 Katoh M, Katoh M. claudin23 gene, frequently down-regulated in intestinal-type gastric cancer, is a novel member of CLAUDIN gene family. Int J Mol Med.2003; 11:683-689
36 Egami H, Takiyama Y, Cano M, et al. Establishment of hamster pancreatic ductal carcinoma cell line (PC-1) producing blood group-related antigens. Carcinogenesis.1989;10:861-869.
37 Egami H, Tomioka T, Tempero M, et al. Development of intrapancreatic transplantable model of pancreatic duct adenocarcinoma in syrian golden hamsters. Am J Pathol.1991; 138: 557-561.
38 Pour PM, Egami H, Takiyama Y. Patterns of growth and metastases of induced pancreatic cancer in relation to the prognosis and its clinical implications. Gastroenterology.1991; 100: 529-536.
39 Kurizaki T, Egami H, Hirota M, et al. Characterization of cancer cell dissociation factor in a highly invasive pancreatic cancer cell line. Cancer.1995 75:1554-1561.
40 Hinshaw JE, Carragher BO, Milligan RA, et al. Architecture and design of the nuclear pore complex. Cell.1992; 69:1133-1141
41 Akey, C.W. and Radermacher, M. Architecture of the Xenopus nuclear pore complex revealed by three-dimensional cryo-electron microscopy. J. Cell Biol.1993; 122:1-19
42 Stoffler, D, Feja B, Fahrenkrog B, et al. Cryo-electron tomography provides novel insights into nuclear pore architecture:implications for nucleocytoplasmic transport. J. Mol. Biol. 2003;328:119-130
43 Yang Q, Rout MP, Akey CW. Three-dimensional architecture of the isolated yeast nuclear pore complex:functional and evolutionary implications. Mol. Cell.1998;223-234
44 Birthe Fahrenkrog, Joachim Koser and Ueli Aebi.he nuclear pore complex:a jack of all trades? TRENDS in Biochemical Sciences.2004;29:175-182
45 D'angelo Ma, Hetzer MW. Structure, dynamics and function of nuclear pore complexes. Trends Cell Biol.2008; 18:456-466
46 Weis K. nuclear pore complex:oily spaghetti or gummy bear? Cell.2007; 130:405-407
47 Cronshaw JM, Krutchinsky an, zhang W, et al. Proteomic analysis of the mammalian nuclear pore complex. J Cell Biol.2002; 158:915-927
48 Mythili Suntharalingaml, and Susan R Wente.Peering through the pore:nuclear pore complex structure, assembly, and function. Dev Cell.2003;4:775-789.
49 Kurt E. Gustin.hibition of nucleo-cytoplasmic trafficking by RNA viruses:targeting the nuclear pore complex. Virus Res.2003;95:35-44.
50 Gustin KE, Sarnow P.Effects of poliovirus infection on nucleo-cytoplasmic trafficking and nuclear pore complex composition. EMBO J.2001; 20:240-249.
51 Ball JR, Ullman KS.Versatility at the nuclear pore complex:lessons learned from the nucleoporin Nup153. Chromosoma.2005;114:319-330
52 Meier i, Brkljacic J. the nuclear pore and plant development. Curr Opin Plant Biol.2009; 12: 87-95
53 akhtar a, gasser SM. the nuclear envelope and transcriptional control. Nat Rev Genet.2007; 8: 507-517,
54 Brown cr, Kennedy cJ, Delmar Va, Forbes DJ, Silver pa. global histone acetylation induces functional genomic reorganization at mammalian nuclear pore complexes. Genes Dev.2008;22: 627-639
55 Schuldt A. Nuclear pore assembly:locating the linchpin. Nat Cell Biol.2003; 5:497-501.
56 Harel A, Orjalo AV, Vincent T, et al. Removal of a Single Pore Subcomplex Results in Vertebrate Nuclei Devoid of Nuclear Pores. Molecular Cell.2003; 11:853-864.
57 Antonin, W., Franz, C., Haselmann, U., et al. The integral membrane nucleoporin poml21 functionally links nuclear pore complex assembly and nuclear envelope formation. Mol. Cell. 2005;17,83-92.
58 D Angelo, M.A., Anderson, D.J., et al. Nuclear pores form de novo from both sides of the nuclear envelope. Science.2006;312,440-443.
59 Maul GG.uclear pore complexes. Elimination and reconstruction during mitosis. J Cell Biol. 1977;74:492-500.
60 Walther TC, Alves A, Pickersgill H, Loiodice I, Hetzer M. The conserved Nup107-160 complex is critical for nuclear pore complex assembly.Cell.2003;113:195-206.
61 Torimura T, Ueno T, Kin M, et al. Autocrine motility factor enhances hepatoma cell invasion across the basement membrane through activation of β1 integrins. Hepatology.2001;34: 62-71,
62 Fincham VJ, James M, Frame MC, et al. Active ERK/MAP kinase is targeted to newly forming cell-matrix adhesions by integrin engagement and v-Src. EMBO J.2000; 19:2911-2923
63 Rescan C, Coutant A, Talarmin H, et al. Mechanism in the sequential control of cell morphology and S phase entry by epidermal growth factor involves distinct MEK/ERK activations. Mol Biol Cell.2001; 12:725-738
64 Farquhar MG and Palade GE.Junctional complexes in various epithelia[J]. Cell Biol.1963;1 7:375-412.
65 Diamond J.The epithelial junction.bridge,gate,and fence[J]. Physiologist,1997,20:10-18.
66 Lynne AL:The molecular structure of the tight junction[J].Adv Drug Deliv Rev.2000;41:155-164.
67 Sonoda N,Furuse M,Sasaki H, et al.Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands:evidence for direct involvement of claudins in tight junction barrier [J]. Cell Biol.1999;147:195-204.
68 Itoh M, Furuse M, Morita K, et al.Direct binding of three tight junction-associated MAGUKs,ZO-1,ZO-2,ZO-3,with the COOH termni of claudins[J]. Cell Biol 1999;147:1351-1363.
69 Michlig S, Damak S, Coutre JL. Claudin-based permeability barriers in taste buds. J Comp Neurol.2007;502:1003-1011
70 Hirota M, Egami H, Corra S, et al. Production of scatter factor-like activity by a nitrosamine-induced pancreatic cancer cell line. Carcinogenesis.1993; 14:259-264
71 Kurizaki T, Egami H, Hirota M, et al. Characterization of cancer cell dissociation factor in a highly invasive pancreatic cancer cell line. Cancer.1995;75:1554-1561
72 Ishikawa S, Egami H, Kurizaki T, et al. Analysis of the factor related to the signal transduction pathway of invasion and metastasis in pancreatic cancer. J Exp Clin Cancer Res.2003; 22: 299-306
73 Tan X, Egami H, Kamohara H, et al. Involvement of the mitogen-activated protein kinase kinase 2 in the induction of cell dissociation in pancreatic cancer. Int J Oncol.2004; 24:65-73
74 Tan X, Egami H, Ishikawa S, et al:. Relationship between the expression of extracellular signal-regulated kinase 1/2 and the dissociation of pancreatic cancer cells:involvement of ERK1/2 in the dissociation status of cancer cells. Int J Oncol.2004;24:815-820
75 D'Souza T, Agarwal R, Morin PJ. Phosphorylation of claudin-3 at threonine 192 by cAMP-dependent protein kinase regulates tight junction barrier function in ovarian cancer cells. J Biol Chem.2005; 280:26233-26240
76 Stamatovic SM, Dimitrijevic OB, Kepp RF, et al. Protein kinase C a-RhoA cross talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem.2006;281: 8379-8388
77 Yamauchi K, Rai T, Kobayashi K, et al.Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proc Natl Acad Sci U S A.2004; 101: 4690-4694
1 Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in respectable pancreatic cancer:a randomised controlled trial. Lancet 2001; 358:1576-1585
2 DiMagno EP, Reber HA and Tempero MA.AGA technical review on the epidemiology, diagnosis, and treatment of pancreatic ductal adenocarcinoma. Gastroenterolgy 1999; 117:1464-1484
3 Kim J, Yu W, Kovalski K and Ossowski L.Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay. Cell 1998; 94:353-362
4 Hanahan D and Weinberg RA. The hallmarks of cancer. Cell 2000,100:57-70
5 Bishop JM. Molecular themes in oncogenesis. Cell 1991; 64:235-248
6 Cavenee WK, Dryja TP, Phillips RA, et al.Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 1983; 305:779-784
7 Ponder B Cancer. Gene losses in human tumours. Nature 1988; 335:400-402
8 Kinzler KW and Vogelstein B.Life (and death) in a malignant tumour.Nature 1996; 379:19-20
9 Brat DJ, Lillemoe KD, Yeo CJ, et al.Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol 1998; 22:163-169
10 Muller A, Homey B, Soto H, et al.Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410:50-56
11 Borsig L, Wong R, Hynes RO, et al. Synergistic effectsof L- and P-selectin in facilitating tumor metastasis can involve non-mucin ligands and implicate leukocytes as enhancersof metastasis. Proc Natl Acad Sci U S A 2002;99:2193-2198
12 Tawil NJ, Gowri V, Djoneidi M, et al. Integrin alpha3beta1 can promote adhesion and spreading of metastatic breast carcinoma cells on the lymph node stroma. Int J Cancer 1996; 66:703-710
13 Siesser PF, Maness PF. L1 cell adhesion molecules as regulators of tumor cell invasiveness. Cell Adh Migr.2009; 3:275-277
14 Francavilla C, Maddaluno L, Cavallaro U. The functional role of cell adhesion molecules in tumor angiogenesis. Semin Cancer Biol.2009;19:298-309
15 Hanahan D, Bergers G and Bergsland E.Less is more, regularly:metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000; 105:1045-1047
16 Aplin AE, Howe A, Alahari SK and Juliano RL.Signal transduction and signal modulation by cell adhesion receptors:the role of integrins, cadherins, immunoglobulin-cell adhesion molecules, and selectins. Pharmacol Rev 1998; 50:197-263
17 Christofori G and Semb H.The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 1999;24:73-76
18 Karayiannakis AJ, Syrigos KN, Polychronidis A and Simopoulos C.Expression patterns of alpha-, beta- and gamma-catenin in pancreatic cancer:correlation with E-cadherin expression, pathological features and prognosis. Anticancer Res 2001,21:4127-4134
19 Skubitz AP.Adhesion molecules. Cancer Treat Res 2002; 107:305-329
20 Maurer CA, Friess H, Kretschmann B, et al.Over-expression of ICAM-1, VCAM-1 and ELAM-1 might influence tumor progression in colorectal cancer. Int J Cancer 1998; 79:76-81
21 Fogar P, Basso D, Pasquali C, et al. Neural cell adhesion molecule (N-CAM) in gastrointestinal neoplasias. Anticancer Res 1997; 17:1227-1230
22 Tempia-Caliera AA, Horvath LZ, Zimmermann A, et al. Adhesion molecules in human pancreatic cancer. J Surg Oncol 2002; 79:93-100
23 Varner JA and Cheresh DA. Integrins and cancer. Curr Opin Cell Biol 1996; 8:724-730
24 Coussens LM and Werb Z. Matrix metalloproteinases and the development of cancer. Chem Biol 1996; 3:895-904
25 Bloomston M, Zervos EE and Rosemurgy AS.Matrix metalloproteinases and their role in pancreatic cancer:a review of preclinical studies and clinical trials. Ann Surg Oncol 2002; 9:668-674
26 Bergers G, Brekken R, McMahon G, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2000; 2:737-744
27 Wang Y.The role and regulation of urokinase-type plasminogen activator receptor gene expression in cancer invasion and metastasis. Med Res Rev 2001; 21:146-170
28 Dano K, Andreasen PA, Grondahl-Hansen J, et al. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 1985; 44:139-266
29 Friess H, Cantero D, Graber H, et al.Enhanced urokinase plasminogen activation in chronic pancreatitis suggests a role in its pathogenesis. Gastroenterology.1997; 113:904-913
30 Bramhall SR, Neoptolemos JP, Stamp GW and Lemoine NR.Imbalance of expression of matrix metalloproteinases (MMPs) and tissue inhibitors of the matrix metalloproteinases (TIMPs) in human pancreatic carcinoma. J Pathol 1997; 182:347-355
31 Blasi F, Sidenius N. The urokinase receptor:focused cell surface proteolysis, cell adhesion and signaling. FEBS Lett.2010;584:1923-1930.
32 Lamy PJ, Romieu G, Jacot W. UPA/PAI-1:a tool for breast cancer treatment individualization. Biology, clinical implications and quantification assays. Bull Cancer.2010;97:341-348.
33 Cantero D, Friess H, Deflorin J, et al.Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma. Br J Cancer 1997; 75:388-395
34 Smith HW, Marshall CJ. Regulation of cell signalling by uPAR. Nat Rev Mol Cell Biol. 2010;11:23-36.
35 Kleiner DE and Stetler-Stevenson WG.Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol 1999;43(Suppl):S42-S51
36 Yoon SO, Park SJ, Yun CH, et al. Roles of matrix metalloproteinases in tumor metastasis and angiogenesis. J Biol Mol Biol.2003;36:128-37.
37 Lohi J, Wilson CL, Roby JD, et al. Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury. J Biol Chem 2001;276:10134-44.
38 38 Cheng K, Xie G, Raufman JP. Matrix metalloproteinase-7-catalyzed release of HB-EGF mediates deoxycholyltaurine-induced proliferation of a human colon cancer cell line. Biochem Pharmacol.2007;73:1001-12
39 Mimori K, Yamashita K, Ohta M, et al. Coexpression of matrix metalloproteinase-7 (MMP-7) and epidermal growth factor (EGF) receptor in colorectal cancer:An EGF receptor tyrosine kinase inhibitor is effective against MMP-7-expressing cancer cells. Clin Cancer Res. 2004; 10:8243-9.
40 Zeng ZS, Shu WP, Cohen AM, et al. Matrix metalloproteinase-7 expression in colorectal cancer liver metastasis:evidence for involvement of MMP-7 activation in human cancer metastasis. Clin Cancer Res.2002;8:144-8.
41 Yamamoto H, Itoh F, Iku S, et al. Expression of matrix metalloproteinases and tissue inhibitors of metatlloproteinases in human pancreatic adenocarcinomas:clinicopathologic and prognostic significance of matrilysin expression. J Clin Oncol.2001; 19:1118-27.
42 Roztocil E, Nicholl SM, Galaria II, et al. Plasmin-induced smooth muscle cell proliferation requires epidermal growth factor activation through an extracellular pathway. Surgery. 2005;138:180-6.
43 Lijnen HR, Collen D. Matrix metalloproteinase system deficiencies and matrix degradation. Thromb Haemost.1999;82:837-45.
44 Yamamoto H, Iku S, Adachi Y, et al. Association of trypsin expression with tumor progression and matrilysin expression in human colorectal cancer. J Pathol.2003; 199:176-84.
45 Moilanen M, Sorsa T, Stenman M, et al. Tumor-associated trypsinogen-2 (trypsinogen-2) activates procollagenases (MMP-1,-8,-13) and stromelysin-1 (MMP-3) and degrades type 1 collag. Biochemistry.2003;42:5414-20.
46 Tan X, Egami H, Abe M, et al. Involvement of matrix metalloproteinase-7 in invasion of pancreatic cancer cells through activation of EGFR-mediated MEK/ERK signal transduction pathway. J Clin Pathol.2005;58:1242-8.
47 Matsuyama Y, Takao S and Aikou T. Comparison of matrix metalloproteinase expression between primary tumors with or without liver metastasis in pancreatic and colorectal carcinomas. J Surg Oncol 2002; 80:105-110
48 Gress TM, Muller-Pillasch F, Lerch MM, et al. Expression and in-situ localization of genes coding for extracellular matrix proteins and extracellular matrix degrading proteases in pancreatic cancer. Int J Cancer 1995;62:407-413
49 Joergensen MT, Brunner N, De Muckadell OB. Comparison of circulating MMP-9, TIMP-1 and CA19-9 in the detection of pancreatic cancer. Anticancer Res.2010;30:587-592.
50 Han F, Zhu HG. Caveolin-1 regulating the invasion and expression of matrix metalloproteinase (MMPs) in pancreatic carcinoma cells. J Surg Res.2010;159:443-450
5151. Mroczko B, Lukaszewicz-Zajac M, Wereszczynska-Siemiatkowska U, et al.. Clinical significance of the measurements of serum matrix metalloproteinase-9 and its inhibitor (tissue inhibitor of metalloproteinase-1) in patients with pancreatic cancer:metalloproteinase-9 as an independent prognostic factor. Pancreas.2009;38:613-618.
52 Beatrice S.Knudsen, George Vande Woude.Showering c-MET-dependent cancers with drugs.Current Opinion in Genetics & Development.2008; 18:87-96
53 Paolo M.Comoglio, Livio Trusolino. Invasive growth:from development to metastasis. J Clin Invest.2002; 109:857-862
54 Guo A, Villen J, Kornhauser J, Lee KA, et al. Signaling networks assembled by oncogenic EGFR and c-MET. Proc Natl Acad Sci U S A 2008; 105:692-697.
55 Smallbone K, Gatenby RA, Gillies RJ, et al. Metabolic changes during carcinogenesis: potential impact on invasiveness. J Theor Biol 2007;244:703-713.
56 Osada S, Matsui S, Komori S, et al. Effect of hepatocyte growth factor on progression of liver metastasis in colorectal cancer. Hepatogastroenterology.2010;57:76-80.