Ezrin与胰腺癌发生、侵袭及转移关系的探讨
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摘要
胰腺癌是预后最差、死亡率最高的恶性肿瘤之一。由于发病部位的特殊性及症状的隐匿性,很难进行早期诊断,绝大多数病例在诊断时已处于晚期。
胰腺癌极强的侵袭和转移能力与其预后差直接相关。手术切除是目前获得治愈的唯一手段,但只有不到20%的患者适于手术切除,而不能手术的患者平均生存时间少于六个月。胰腺癌预后差的原因之一是常在出现临床症状和影像学技术改变之前就有微转移灶形成。研究胰腺癌的这种高度恶性生长扩散方式的机制,从而找到治疗胰腺癌的新方法,是目前医学研究的迫切任务之一。
近年文献报道,ezrin的高表达可以促进多种肿瘤的转移,因此ezrin可能是某些肿瘤基因治疗的潜在靶点。越来越多的研究表明ezrin在肿瘤细胞中的生物学行为中发挥着重要的作用。通过干预ezrin表达探讨ezrin对胰腺癌细胞生物学行为的影响,目前尚未有研究报道。
本研究旨在利用RNA干扰技术和基因过表达技术对胰腺癌细胞系MiaPaCa-2细胞中ezrin的表达进行干预,进而探讨ezrin对胰腺癌生物学行为的影响。
1.利用RNA干扰技术研究ezrin在胰腺癌细胞的表达抑制后对细胞生物学行为的影响:成功确立了ezrin的有效干扰位点,构建干扰载体,并挑选出稳定干扰克隆。发现ezrin表达抑制对胰腺癌的增殖和细胞周期没有明显的影响,但ezrin表达抑制可使胰腺癌细胞的细胞突起和表面微绒毛明显减少,在软琼脂内形成克隆数明显减少,细胞迁移至Transwell Chambers下室的数量明显下降,侵袭至Matrigel Invasion Chambers下室的细胞数量明显减少。
2.利用ezrin表达载体对胰腺癌细胞MiaPaCa-2进行转染,筛选获得稳定过表达克隆。发现ezrin过表达对胰腺癌细胞的增殖和细胞周期没有明显的影响,但ezrin过表达可使胰腺癌细胞的细胞突起和微绒毛明显增多,在软琼脂内形成的克隆数明显增多,细胞迁移至Transwell Chambers下室的数量增加,侵袭至Matrigel Invasion Chambers下室的细胞增多。
3.利用明胶酶谱分析发现,ezrin过表达可引起基质金属蛋白酶MMP-9的表达,但ezrin敲减表达对明胶酶表达的影响并不明显;对Akt及Erk1/2信号通路的分析表明,ezrin的过表达可使Erk1/2磷酸化水平降低,而ezrin敲减表达对Erk1/2磷酸化水平的影响不明显,ezrin的表达变化对Akt的磷酸化水平,Akt总蛋白和Erk1/2总蛋白影响不明显,此结果提示ezrin可能通过下调Erk1/2的磷酸化水平,进而导致肌动蛋白细胞骨架的重现从而引起细胞运动能力的增加,进而导致细胞侵袭能力的改变;而ezrin表达下调引起细胞运动和侵袭能力的下降可能还通过其它机制。
综上所述,本研究发现ezrin的表达变化可引起细胞伪足及表面微绒毛数量、细胞运动、侵袭能力的改变和细胞非锚定依赖性的生长能力的改变,表明ezrin蛋白在这些细胞生物学行为方面发挥着重要的作用。Ezrin引起肿瘤细胞侵袭和运动能力的变化部分可能是通过影响Erk1/2磷酸化水平引起肌动蛋白细胞骨架的重构,继而导致细胞运动能力的改变引起的,部分可能是通过引起MMP的表达变化导致其侵袭能力的改变所致,具体的机制还需要进一步研究。
Ezrin在胰腺癌的形态学、非锚定依赖性的生长、运动以及侵袭转移过程中发挥着重要的作用。因此,针对ezrin表达的干预可能会使胰腺癌肿瘤细胞侵袭和转移能力下降,有希望成为胰腺癌侵袭转移的一个新的治疗靶点,从而为胰腺癌的治疗提供了一条新的途径。
Pancreatic ductal ademocarcinoma is the eighth leading cause of cancer mortality in China and the fourth in United States. The incidence of Pancreatic ductal ademocarcinoma is increasing. So far neither an early diagnosis nor a therapeutic strategy for advanced lesions has been developed yet. The death to incidence ratio of pancreatic ductal carcinoma is approximate to 0.98-0.993. The overall 5-year survival rate of pancreatic carcinoma is less than 5%, which is largely due to the difficulty in early diagnosis. More than 85% of patients have the disease extending beyond the pancreas at the time of diagnosis, rendering surgical and medical intervention ineffective. For the 15-20% of patients who undergo potentially curative resection, the 5-year survival is only 20%. It is an urgent mission for both the clinicians and the scientists who devote themselves to pancreatic cancer to find a breakthrough using new techniques.
Ezrin is a member of the ERM family, it provides a functional link between the plasma membrane and the cortical actin cytoskeleton of the cell, and participates in crucial signal transduction pathways. There are increasing evidences that it can regulate tumor progression and metastasis. However, the role of ezrin in pancreatic cancer has not clearly delineated.
Ezrin expression leval was interrupted in pancreatic cancer cells MiaPaCa-2 by ezrin knock-down and overexpression, and the biological behavior changes in these cells were observed and analyzed.
1. Knock-down ezrin expression in pancreatic cancer cells MiaPaca-2 by RNAi: The suppression of ezrin did not influence cells proliferation and the cell cycle in vitro; but ezrin depression can inhibit the formation of cell protrusion and cell microvilli as well as cause a decrease in cell motility and invasiveness. Furthermore, we revealed that ezrin silencing can reduce the anchorage-independent growth of the tumor cells in soft agar.
2. Ezrin overexpression in pancreatic cancer cells MiaPaca-2: The overexpression of ezrin did not influence cells proliferation and the cell cycle in vitro; but it can enhance the formation of cell protrusion and cell microvilli as well as cause an increase in cell motility and invasiveness. Furthermore, we revealed that ezrin overexpression can raise the ability of the anchorage-independent growth of the tumor cells in soft agar.
3. Gelatin zymography assay revealed that overexpression of ezrin can induce the expression of MMP-9, but the effect of ezrin knock-down on the expression of gelatinase is not obvious. Ezrin overexpression can also induce the activation of Erkl/2, but ezrin silencing can not influence the activation of Erkl/2. The alteration of ezrin expression could not influence the Akt activation, total Akt as well as total Erkl/2 protein level. There may be another pathway involved in ezrin induced pancreatic ductal adenocarcinoma cells motiliy and invasiness.
Our experiments showed that the alteration of ezrin expression can induce the changes in cell protrusion and cell microvilli, cell motility, invasiveness as well as the ability of the anchorage-independent growth of the tumor cells. The inactivation of Erkl/2 may induce the actin cytoskeleton reappearance and contribute to alteration of cell motility and invasiveness ability. The latter may be related to induced MMP-9 expression when ezrin was overexpressed.
Consistent with these results, ezrin may be an important target for inhibiting the invasion and metastasis of pancreatic ductal adenocarcinoma.
胰腺癌极强的侵袭和转移能力与其预后差直接相关。手术切除是目前获得治愈的唯一手段,但只有不到20%的患者适于手术切除,而不能手术的患者平均生存时间少于六个月。胰腺癌预后差的原因之一是常在出现临床症状和影像学技术改变之前就有微转移灶形成。研究胰腺癌的这种高度恶性生长扩散方式的机制,从而找到治疗胰腺癌的新方法,是目前医学研究的迫切任务之一。
近年文献报道,ezrin的高表达可以促进多种肿瘤的转移,因此ezrin可能是某些肿瘤基因治疗的潜在靶点。越来越多的研究表明ezrin在肿瘤细胞中的生物学行为中发挥着重要的作用。通过干预ezrin表达探讨ezrin对胰腺癌细胞生物学行为的影响,目前尚未有研究报道。
本研究旨在利用RNA干扰技术和基因过表达技术对胰腺癌细胞系MiaPaCa-2细胞中ezrin的表达进行干预,进而探讨ezrin对胰腺癌生物学行为的影响。
1.利用RNA干扰技术研究ezrin在胰腺癌细胞的表达抑制后对细胞生物学行为的影响:成功确立了ezrin的有效干扰位点,构建干扰载体,并挑选出稳定干扰克隆。发现ezrin表达抑制对胰腺癌的增殖和细胞周期没有明显的影响,但ezrin表达抑制可使胰腺癌细胞的细胞突起和表面微绒毛明显减少,在软琼脂内形成克隆数明显减少,细胞迁移至Transwell Chambers下室的数量明显下降,侵袭至Matrigel Invasion Chambers下室的细胞数量明显减少。
2.利用ezrin表达载体对胰腺癌细胞MiaPaCa-2进行转染,筛选获得稳定过表达克隆。发现ezrin过表达对胰腺癌细胞的增殖和细胞周期没有明显的影响,但ezrin过表达可使胰腺癌细胞的细胞突起和微绒毛明显增多,在软琼脂内形成的克隆数明显增多,细胞迁移至Transwell Chambers下室的数量增加,侵袭至Matrigel Invasion Chambers下室的细胞增多。
3.利用明胶酶谱分析发现,ezrin过表达可引起基质金属蛋白酶MMP-9的表达,但ezrin敲减表达对明胶酶表达的影响并不明显;对Akt及Erk1/2信号通路的分析表明,ezrin的过表达可使Erk1/2磷酸化水平降低,而ezrin敲减表达对Erk1/2磷酸化水平的影响不明显,ezrin的表达变化对Akt的磷酸化水平,Akt总蛋白和Erk1/2总蛋白影响不明显,此结果提示ezrin可能通过下调Erk1/2的磷酸化水平,进而导致肌动蛋白细胞骨架的重现从而引起细胞运动能力的增加,进而导致细胞侵袭能力的改变;而ezrin表达下调引起细胞运动和侵袭能力的下降可能还通过其它机制。
综上所述,本研究发现ezrin的表达变化可引起细胞伪足及表面微绒毛数量、细胞运动、侵袭能力的改变和细胞非锚定依赖性的生长能力的改变,表明ezrin蛋白在这些细胞生物学行为方面发挥着重要的作用。Ezrin引起肿瘤细胞侵袭和运动能力的变化部分可能是通过影响Erk1/2磷酸化水平引起肌动蛋白细胞骨架的重构,继而导致细胞运动能力的改变引起的,部分可能是通过引起MMP的表达变化导致其侵袭能力的改变所致,具体的机制还需要进一步研究。
Ezrin在胰腺癌的形态学、非锚定依赖性的生长、运动以及侵袭转移过程中发挥着重要的作用。因此,针对ezrin表达的干预可能会使胰腺癌肿瘤细胞侵袭和转移能力下降,有希望成为胰腺癌侵袭转移的一个新的治疗靶点,从而为胰腺癌的治疗提供了一条新的途径。
Pancreatic ductal ademocarcinoma is the eighth leading cause of cancer mortality in China and the fourth in United States. The incidence of Pancreatic ductal ademocarcinoma is increasing. So far neither an early diagnosis nor a therapeutic strategy for advanced lesions has been developed yet. The death to incidence ratio of pancreatic ductal carcinoma is approximate to 0.98-0.993. The overall 5-year survival rate of pancreatic carcinoma is less than 5%, which is largely due to the difficulty in early diagnosis. More than 85% of patients have the disease extending beyond the pancreas at the time of diagnosis, rendering surgical and medical intervention ineffective. For the 15-20% of patients who undergo potentially curative resection, the 5-year survival is only 20%. It is an urgent mission for both the clinicians and the scientists who devote themselves to pancreatic cancer to find a breakthrough using new techniques.
Ezrin is a member of the ERM family, it provides a functional link between the plasma membrane and the cortical actin cytoskeleton of the cell, and participates in crucial signal transduction pathways. There are increasing evidences that it can regulate tumor progression and metastasis. However, the role of ezrin in pancreatic cancer has not clearly delineated.
Ezrin expression leval was interrupted in pancreatic cancer cells MiaPaCa-2 by ezrin knock-down and overexpression, and the biological behavior changes in these cells were observed and analyzed.
1. Knock-down ezrin expression in pancreatic cancer cells MiaPaca-2 by RNAi: The suppression of ezrin did not influence cells proliferation and the cell cycle in vitro; but ezrin depression can inhibit the formation of cell protrusion and cell microvilli as well as cause a decrease in cell motility and invasiveness. Furthermore, we revealed that ezrin silencing can reduce the anchorage-independent growth of the tumor cells in soft agar.
2. Ezrin overexpression in pancreatic cancer cells MiaPaca-2: The overexpression of ezrin did not influence cells proliferation and the cell cycle in vitro; but it can enhance the formation of cell protrusion and cell microvilli as well as cause an increase in cell motility and invasiveness. Furthermore, we revealed that ezrin overexpression can raise the ability of the anchorage-independent growth of the tumor cells in soft agar.
3. Gelatin zymography assay revealed that overexpression of ezrin can induce the expression of MMP-9, but the effect of ezrin knock-down on the expression of gelatinase is not obvious. Ezrin overexpression can also induce the activation of Erkl/2, but ezrin silencing can not influence the activation of Erkl/2. The alteration of ezrin expression could not influence the Akt activation, total Akt as well as total Erkl/2 protein level. There may be another pathway involved in ezrin induced pancreatic ductal adenocarcinoma cells motiliy and invasiness.
Our experiments showed that the alteration of ezrin expression can induce the changes in cell protrusion and cell microvilli, cell motility, invasiveness as well as the ability of the anchorage-independent growth of the tumor cells. The inactivation of Erkl/2 may induce the actin cytoskeleton reappearance and contribute to alteration of cell motility and invasiveness ability. The latter may be related to induced MMP-9 expression when ezrin was overexpressed.
Consistent with these results, ezrin may be an important target for inhibiting the invasion and metastasis of pancreatic ductal adenocarcinoma.
引文
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59. Serrador JM, Nieto M, Alonso-Lebrero JL, et al. CD43 interacts with moesin and ezrin and regulates its redistribution to the uropods of T lymphocytes at the cell-cell contacts. Blood, 1998, 91(12):4632-4644.
60. Helander TS, Carpen O, Turunen O, et al. ICAM-2 redistributed by ezrin as a target for killer cells. Nature, 1996, 382(6588):265-268.
61. Poullet P, Gautreau A, Kadare G, et al. Ezrin interacts with focal adhesion kinase and induces its activation independently of cell-matrix adhesion. J Biol Chem, 2001, 276(40):37686-37691.
62. Reddy KB, Nabha SM, Atanaskova N. Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev, 2003, 22(4):395-403.
63. Barros JC, Marshall CJ. Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton.J Cell Sci, 2005, 118(Pt8):1663-1671.
1. Hanahan D, Weinberg RA. The Hallmarks of Cancer. Cell, 2000, 100(1):57-70.
2. Hezel AF, Kimmelman AC, Stanger BZ, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev, 2006, 20(10): 1218-1249.
3. Liu B, Lu KY. Neural invasion in pancreatic carcinoma. Hepatobiliary Pancreat Dis Int, 2002, 1(3):469-476.
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5. Curto M, McClatchey Al. Ezrin.. .a metastatic detERMinant? Cancer Cell,2004, 5(2):113-114.
6. Louvet-Vallee S. ERM proteins: from cellular architecture to cell signaling. Biol Cell, 2000, 92(5):305-316.
7. Bretscher A, Edwards K. Fehon RG. ERM proteins and merlin: integrators at the cell cortex. Nat Rev Mol Cell Biol, 2002, 3(8):586-599.
8. Tsukita S, Yonemura S. ERM (ezrin/radixin/moesin) family: from cytoskeleton to signal transduction. Curr Opin Cell Biol, 1997;9(1):70-75.
9. Majander-Nordenswan P, Sainio M, Turunen O, et al. Genomic structure of the human ezrin gene. Hum Genet, 1998, 103(6):662-665.
10. Algrain M, Turunen O, Vaheri A, et al. Ezrin Contains Cytoskeleton and Membrane Binding Domains Accounting for its Proposed Role as a Membrane-Cytoskeletal Linker. The Journal of Cell Biology, 1993,120(1):129-139.
11. Turunen O, Wahlstrom T, Vaheri A. Ezrin has a COOH-terminal actin-binding site that is conserved in the ezrin protein family J Cell Biol.1994 ;126(6):1445-1453.
12. Andreoli C, Martin M, Le Borgne R, et al. Ezrin has properties to self-associate at the plasma membrane. J Cell Sci, 1994, 107 ( Pt 9):2509-2521.
13. Arpin M, Algrain M, Louvard D. Membrane-actin microfilament connections: an increasing diversity of players related to band 4.1 Curr Opin Cell Biol, 1994, 6(1): 136-141.
14. Algrain M, Turunen O, Vaheri A, et al. Ezrin contains cytoskeleton and membrane binding domains accounting for its proposed role as a membrane-cytoskeletal linker. J Cell Biol, 1993, 120(1):129-139.
15. Hayashi K, Yonemura S, Matsui T, et al. Immunofluorescence detection of ezrin/radixin/moesin (ERM) proteins with their carboxyl-terminal threonine phosphorylated in cultured cells and tissues. J Cell Sci, 1999,112(Pt8):1149-1158.
16. Yu T, Robb VA, Singh V, et al. The 4.1/ezrin/radixin/moesin domain of the DAL-1/Protein 4.1B tumour suppressor interacts with 14-3-3 proteins.Biochem J, 2002, 365(Pt 3):783-789.
17. Lee JH, Katakai T, Hara T, et al. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J Cell Biol, 2004,167(2): 327-337.
18. Kosako H, Yoshida T, Matsumura F, et al. Rho-kinase/ROCK is involved in cytokinesis through the phosphorylation of myosin light chain and not ezrin/radixin/moesin proteins at the cleavage furrow. Oncogene, 2000,19(52): 6059-6064.
19. Serrador JM, Nieto M, Alonso-Lebrero JL, et al. CD43 interacts with moesin and ezrin and regulates its redistribution to the uropods of T lymphocytes at the cell-cell contacts. Blood, 1998, 91(12):4632-4644.
20. Poullet P, Gautreau A, Kadare G, et al. Ezrin interacts with focal adhesion kinase and induces its activation independently of cell-matrix adhesion. J Biol Chem, 2001, 276(40):37686-37691.
21. Shen ZY, Xu LY, Chen MH, et al. Upregulated expression of Ezrin and invasive phenotype in malignantly transformed esophageal epithelial cells.World J Gastroenterol, 2003, 9(6): 1182-1186.
22. Valdman A, Fang X, Pang ST, et al. Ezrin expression in prostate cancer and benign prostatic tissue. Eur Urol, 2005, 48(5):852-857.
23. Wan X, Mendoza A, Khanna C, et al. Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma. Cancer Res, 2005,65(6):2406-2411.
24. Ilmonen S, Vaheri A, Asko-Seljavaara S, et al. Ezrin in primary cutaneous melanoma. Mod Pathol, 2005, 18(4):503-510.
25. Weng WH, Ahlen J, Astrom K, et al. Prognostic impact of immunohistochemical expression of ezrin in highly malignant soft tissue sarcomas. Clin Cancer Res, 2005,11(17):6198-6204.
26. Elliott BE, Meens JA, SenGupta SK, et al. The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells.Breast Cancer Res, 2005, 7(3):R365-373.
27. Kishore R, Qin G, Luedemann C, et al. The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin A. J Clin Invest, 2005, 115(7):1785-1796.
28. Pang ST, Fang X, Valdman A, et al. Expression of ezrin in prostatic intraepithelial neoplasia. Urology, 2004, 63(3):609-612.
29. Tseng JH, Liu NJ, Chen TC, et al. Significance of cellular distribution of ezrin in pancreatic cystic neoplasms and ductal adenocarcinoma. Arch Surg, 2005,140(12): 1184-1190.
30. Yeh TS, Tseng JH, Liu NJ, et al. Significance of cellular distribution of ezrin in pancreatic cystic neoplasms and ductal adenocarcinoma. Arch Surg, 2005, 140(12):1184-1190.
31. Kitamura N, Iwamura T, Taniguchi S, et al. High collagenolytic activity in spontaneously highly metastatic variants derived from a human pancreatic cancer cell line (SUIT-2) in nude mice. Clin Exp Metastasis, 2000, 18(7):561-571.
32. Akisawa N, Nishimori I, Iwamura T, et al. High levels of ezrin expressed by human pancreatic adenocarcinoma cell lines with high metastatic potential. Biochem Biophys Res Commun, 1999, 258(2): 395-400.
33. Yu Y, Khan J, Khanna C, et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med, 2004, 10(2): 175-181.
34. Khanna C, Wan X, Bose S, et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med, 2004,10(2): 182-186.
35. Berryman M, Franck Z, Bretscher A. Ezrin is concentrated in the apical microvilli of a wide variety of epithelial cells whereas moesin is found primarily in endothelial cells. J Cell Sci, 1993,105(Pt4):1025-1043.
36. Peltonl PD, Shermanl LS, Rizvil TA, et al. Ruffling membrane, stress fiber, cell spreading and proliferation abnormalities in human Schwannoma cells. Oncogene, 1998, 17(17):2195 - 2209.
37. Jiang WG, Hiscox S, Singhrao SK, et al. Induction of tyrosine phosphorylation and translocation of ezrin by hepatocyte growth factor/scatter factor. Biochem Biophys Res Commun, 1995, 217(3):1062-1069.
38. Bretscher A. Rapid phosphorylation and reorganization of ezrin and spectrin accompany morphological changes induced in A-431 cells by epidermal growth factor. J Cell Biol, 1989, 108(3):921-930.
39. Crepaldi T, Gautreau A, Comoglio PM, et al. Ezrin is an effector of hepatocyte growth factor-mediated migration and morphogenesis in epithelial cells. J Cell Biol, 1997,138(2):423-434.
40. Stapleton G, Malliri A, Ozanne BW. Downregulated AP-1 activity is associated with inhibition of Protein-Kinase-C-dependent CD44 and ezrin localisation and upregulation of PKC theta in A431 cells. J Cell Sci, 2002,115(Pt 13): 2713-2724.
41. Yang HS, Hinds PW. Phosphorylation of Ezrin by Cyclin- Dependent Kinase 5 Induces the Release of Rho GDP Dissociation Inhibitor to Inhibit Rac1 Activity in Senescent Cells. Cancer Res, 2006, 66 (5): 2708-2715.
42. Granes F, Urena JM, Rocamora N, et al. Ezrin links syndecan-2 to the cytoskeleton. J Cell Sci, 2000, 113 (Pt 7): 1267-1276.
43. Morales FC, Takahashi Y, Kreimann EL, et al. Ezrin-radixin-moesin (ERM)-binding phosphoprotein 50 organizes ERM proteins at the apical membrane of polarized epithelia. Proc Natl Acad Sci USA, 2004,101(51): 17705-17710.
44. Wang H, Guo Z, Wu F, et al. PKA-mediated protein phosphorylation protects ezrin from calpain I cleavage. Biochem Biophys Res Commun,2005, 333(2):496-501.
45. Orian-Rousseau V, Chen L, Sleeman JP, et al. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev, 2002 16(23):3074-3086.
46. Rudzki Z, Jothy S. CD44 and the adhesion of neoplastic cells. Mol Pathol, 1997, 50(2):57-71.
47. Orian-Rousseau V, Morrison H, Matzke A, et al. Hepatocyte growth factor-induced Ras activation requires ERM proteins linked to both CD44v6 and F-actin. Mol Biol Cell, 2007, 18(1):76-83.
48. Calinisan V, Gravem D, Chen RP, et al. New insights into potential functions for the protein 4.1 superfamily of proteins in kidney epithelium. Front Biosci, 2006, 11 (5): 1646-1666.
49. Schlaepfer DD, Hauck CR, Sieg DJ. Signaling through focal adhesion kinase. Prog Biophys Mol Biol, 1999, 71(3-4):435-478.
50. Guo W, Giancotti FG Integrin signalling during tumour progression. Nat Rev Mol Cell Biol, 2004, 5(10):816-826.
51. Ng T, Parsons M, Hughes WE, et al. Ezrin is a downstream effector of trafficking PKC-integrin complexes involved in the control of cell motility.EMBO J, 2001, 20(11):2723-2741.
52. Legg JW, Lewis CA, Parsons M, et al. A novel PKC-regulated mechanism controls CD44 ezrin association and directional cell motility. Nat Cell Biol,2002,4(6):399-407.
53. Martin TA, Harrison G, Mansel RE, et al. The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol, 2003, 46(2):165-186.
54. Tracey A. Martin, Gregory Harrison, et al. The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol, 2003, 46(2):165-186.
55. Hiscox S, Jiang WG Ezrin regulates cell-cell and cell-matrix adhesion, a possible role with E-cadherin/beta-catenin. J Cell Sci, 1999, 112 (Pt 18):3081-3090.
56. Mangeat P, Roy C, Martin M. ERM proteins in cell adhesion and membrane dynamics. Trends Cell Biol, 1999, 9(5): 187-192.
57. Cant SH, Pitcher JA. G Protein-coupled Receptor Kinase 2-mediated Phosphorylation of Ezrin Is Required for G Proteincoupled Receptor-dependent Reorganization of the Actin Cytoskeleton. Mol Biol Cell, 2005,16(7):3088-3099.
58. Yang X, Staren E D, Howard J M, et al. Invasiveness and MMP expression in pancreatic carcinoma. J Surg Res, 2001,98(1):33-39.
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60. Byun HJ, Hong IK, Kim E, et al. A splice variant of CD99 increases motility and MMP-9 expression of human breast cancer cells through the AKT-, ERK-, and JNK-dependent AP-1 activation signaling pathways. J Biol Chem, 2006,281(46):34833-34847.
61. Yu X, Lin SG, Huang XR, et al. Macrophage migration inhibitory factor induces MMP-9 expression in macrophages via the MEK-ERK MAP kinase pathway. J Interferon Cytokine Res, 2007, 27(2): 103-109.
62. Sun HW, Li CJ, Chen HQ, et al. Involvement of integrins, MAPK, and NF-kappaB in regulation of the shear stress-induced MMP-9 expression in endothelial cells. Biochem Biophys Res Commun, 2007, 353(1): 152-158.
63. Liu Y, Smith PW, Jones DR. Breast cancer metastasis suppressor 1 functions as a corepressor by enhancing histone deacetylase 1-mediated deacetylation of RelA/p65 and promoting apoptosis. Mol Cell Biol, 2006,26(23): 8683-8696.
64. Lozupone F, Lugini L, Matarrese P, et al. Identification and relevance of the CD95-binding domain in the N-terminal region of ezrin. J Biol Chem,2004, 279(10): 9199-9207.
65. Gajate C, Mollinedo F. Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy. J Biol Chem, 2005, 280(12):11641-11647.
66. Alfthan K, Heiska L, Gronholm M, et al. Cyclic AMP-dependent protein kinase phosphorylates merlin at serine 518 independently of p21 -activated kinase and promotes merlin-ezrin heterodimerization. J Biol Chem, 2004,279(18): 18559-18566.
67. Lallemand D, Curto M, Saotome I, et al. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev, 2003, 17(9): 1090-1100.
68. McClatchey Al. Merlin and ERM proteins: unappreciated roles in cancer development? Nat Rev Cancer, 2003, 3(11):877-883.
69. Wick W, Grimmel C, Wild-Bode C, et al. Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by BCL-2 and transforming growth factor-beta2. J Neurosci, 2001, 21(10):3360-3368.
70. Khanna C, Khan J, Nguyen P, et al. Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res, 2001,61(9):3750-3759.
71. Li Q, Wu MF, Song AP, et al. Expression of Ezrin and E-cadherin in invasive ductal breast cancer and their correlations to lymphatic metastasis.Ai Zheng, 2006, 25(3):363-366.
72. Guan XQ, Wang CJ, Li YY. Effects of Ezrin on differentiation and adhesion of hepatocellular carcinoma. Ai Zheng, 2002, 21(3):281-284.
73. Nestl A, Von Stein OD, Zatloukal K, et al. Gene expression patterns associated with the metastatic phenotype in rodent and human tumors.Cancer Res, 2001, 61(4):1569-1577.
74. Helander TS, Carpen O, Turunen O, et al. ICAM-2 redistributed by ezrin as a target for killer cells. Nature, 1996, 382(6588):265-268.
75. Reddy KB, Nabha SM, Atanaskova N. Role of MAP kinase in tumor progression and invasion. Cancer Metastasis Rev, 2003, 22(4):395-403.
76. Barros JC, Marshall CJ. Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton. J Cell Sci,2005, 118(Pt 8): 1663-1671.
77. Manchanda N, Lyubimova A, Ho HY, et al. The NF2 tumor suppressor Merlin and the ERM proteins interact with N-WASP and regulate its actin polymerization function. J Biol Chem, 2005, 280(13):12517-12522.
78. Pietromonaco SF, Simons PC, Altaian A, et al. Protein kinase C-theta phosphorylation of moesin in the actin-binding sequence. J Biol Chem,1998,273(13):7594-7603.
79. Srivastava J, Elliott BE, Louvard D, et al. Src-dependent ezrin phosphorylation in adhesion-mediated signaling. Mol Biol Cell, 2005,16(3): 1481-1490.
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2. Ward S, Morris E, Bansback N, et al. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer. Health Technol Assess, 2001,5(24):1-70.
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5. Palesty JA, Dudrick SJ. What we have learned about cachexia in gastrointestinal cancer. Dig Dis 2003, 21(3): 198-213.
6. Turunen O, Wahlstrom T, Vaheri A. Ezrin has a COOH-terminal actin-binding site that is conserved in the ezrin protein family. J Cell Biol, 1994, 126(6): 1445-1453.
7. Andreoli C, Martin M, Le Borgne R, et al. Ezrin has properties to self-associate at the plasma membrane. J Cell Sci, 1994, 107 (Pt 9):2509-2521.
8. Arpin M, Al grain M, Louvard D. Membrane-actin micro filament connections: an increasing diversity of players related to band 4.1. Curr Opin Cell Biol, 1994, 6(1):136-141.
9. Algrain M, Turunen O, Vaheri A, et al. Ezrin contains cytoskeleton and membrane binding domains accounting for its proposed role as a membrane-cytoskeletal linker. J Cell Biol, 1993, 120(1):129-139.
10. Lee JH, Katakai T, Hara T, et al. Roles of p-ERM and Rho-ROCK signaling in lymphocyte polarity and uropod formation. J Cell Biol, 2004,167(2):327-337.
11. Curto M, McClatchey AI. Ezrin...a metastatic detERMinant? Cancer Cell, 2004,5(2):113-114.
12. Valdman A, Fang X, Pang ST, et al. Ezrin expression in prostate cancer and benign prostatic tissue. Eur Urol, 2005,(5):852-857.
13. Wan X, Mendoza A, Khanna C, et al. Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma.Cancer Res, 2005, 65(6):2406-2411.
14. Ilmonen S, Vaheri A, Asko-Seljavaara S, et al. Ezrin in primary cutaneous melanoma. Mod Pathol, 2005, 18(4):503-510.
15. Weng WH, Ahlen J, Astrom K, et al. Prognostic impact of immuno-histochemical expression of ezrin in highly malignant soft tissue sarcomas. Clin Cancer Res, 2005, 11(17):6198-6204.
16. Elliott BE, Meens JA, SenGupta SK, et al. The membrane cytoskeletal crosslinker ezrin is required for metastasis of breast carcinoma cells.Breast Cancer Res, 2005, 7(3):R365-373.
17. Kishore R, Qin G, Luedemann C, et al. The cytoskeletal protein ezrin regulates EC proliferation and angiogenesis via TNF-alpha-induced transcriptional repression of cyclin A. J Clin Invest, 2005, 115(7):1785-1796.
18. Pang ST, Fang X, Valdman A, et al. Expression of ezrin in prostatic intraepithelial neoplasia. Urology, 2004, 63(3):609-612.
19. Tseng JH, Liu NJ, Chen TC, et al. Significance of cellular distribution of ezrin in pancreatic cystic neoplasms and ductal adenocarcinoma.Arch Surg, 2005, 140(12):1184-1190.
20. Kitamura N, Iwamura T, Taniguchi S, et al. High collagenolytic activity in spontaneously highly metastatic variants derived from a human pancreatic cancer cell line (SUIT-2) in nude mice. Clin Exp Metastasis, 2000, 18(7):561-571.
21. Akisawa N, Nishimori I, Iwamura T, et al. High levels of ezrin expressed by human pancreatic adenocarcinoma cell lines with high metastatic potential. Biochem Biophys Res Commun, 1999,258(2):395-400.
22. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell, 2000,100(1): 57-70.
23. Hezel AF, Kimmelman AC, Stanger BZ, et al. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev, 2006, 20(10):1218-1249.
24. Liu B, Lu KY. Neural invasion in pancreatic carcinoma. Hepatobiliary Pancreat Dis Int, 2002, 1(3):469-476.
25. Yu Y, Khan J, Khanna C, et al. Expression profiling identifies the cytoskeletal organizer ezrin and the developmental homeoprotein Six-1 as key metastatic regulators. Nat Med, 2004, 10(2):175-181.
26. Louvet-Vallee S. ERM proteins: from cellular architecture to cell signaling. Biol Cell, 2000, 92(5):305-316.
27. Bretscher A, Edwards K, Fehon RG ERM proteins and merlin:integrators at the cell cortex. Nat Rev Mol Cell Biol, 2002,3(8):586-599.
28. Tsukita S, Yonemura S. ERM (ezrin/radixin/moesin) family: from cytoskeleton to signal transduction. Curr Opin Cell Biol, 1997,9(1):70-75.
29. Khanna C, Wan X, Bose S, et al. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med, 2004,10(2):182-186.
30. Ishikswa R, Yamashiro S, Kohama K, et al. Regulation of actin binding and actin bundling activities of fascin by caldesmon coupled with tropomyosin. J Biol Chem, 1998, 273(41):26991-26997.
31. Manchanda N, Lyubimova A, Ho HY, et al. The NF2 tumor suppressor Merlin and the ERM proteins interact with N-WASP and regulate its actin polymerization function. J Biol Chem, 2005,280(13):12517-12522.
32. Ng T, Parsons M, Hughes WE, et al. Ezrin is a downstream effector of trafficking PKC-integrin complexes involved in the control of cell motility. EMBO J, 2001, 20(11):2723-2741.
33. Kosako H, Yoshida T, Matsumura F, et al. Rho-kinase/ROCK is involved in cytokinesis through the phosphorylation of myosin light chain and not ezrin/radixin/moesin proteins at the cleavage narrow.Oncogene, 2000,19(52):6059-6064.
34. Pietromonaco SF, Simons PC, Altman A, et al. Protein kinase C-theta phosphorylation of moesin in the actin-binding sequence. J Biol Chem,1998,273(13): 7594-7603.
35. Srivastava J, Elliott BE, Louvard D, et al. Src-dependent ezrin phosphorylation in adhesion-mediated signaling. Mol Biol Cell, 2005,16(3): 1481-1490.
36. McClatchey Al. Merlin and ERM proteins: unappreciated roles in cancer development? Nat Rev Cancer, 2003, 3(11):877-883.
37. Orian-Rousseau V, Chen L, Sleeman JP, et al. CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev, 2002, 16(23):3074-3086.
38. Wick W, Grimmel C, Wild-Bode C, et al. Ezrin-dependent promotion of glioma cell clonogenicity, motility, and invasion mediated by BCL-2 and transforming growth factor-beta2. J Neurosci, 2001,21(10):3360-3368.
39. Calinisan V, Gravem D, Chen RP, et al. New insights into potential functions for the protein 4.1 superfamily of proteins in kidney epithelium. Front Biosci, 2006, 11:1646-1666.
40. Schlaepfer D D, Hauck C R, Sieg D J. Signaling through focal adhesion kinase. Prog Biophys Mol Biol, 1999, 71(3-4):435-478.
41. Guo W, Giancotti FG. Integrin signalling during tumour progression.Nat Rev Mol Cell Biol, 2004, 5(10):816-826
42. Legg JW, Lewis CA, Parsons M, et al. A novel PKC-regulated mechanism controls CD44 ezrin association and directional cell motility. Nat Cell Biol, 2002, 4(6):399-407.
43. Martin TA, Harrison G, Mansel RE, et al. The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol, 2003, 46(2):165-186.
44. Hiscox S, Jiang WG Ezrin regulates cell-cell and cell-matrix adhesion,a possible role with E-cadherin/beta-catenin. J Cell Sci, 1999, 112 (Pt 18): 3081-3090.
45. Mangeat P, Roy C, Martin M. ERM proteins in cell adhesion and membrane dynamics. Trends Cell Biol, 1999, 9(5): 187-192.
46. Rudzki Z, Jothy S. CD44 and the adhesion of neoplastic cells. Mol Pathol, 1997, 50(2):57-71.
47. Cant SH, Pitcher JA. G Protein-coupled Receptor Kinase 2-mediated Phosphorylation of Ezrin Is Required for G Proteincoupled Receptor-dependent Reorganization of the Actin Cytoskeleton. Mol Biol Cell, 2005, 16(7):3088-3099.
48. Yang X, Staren E D, Howard J M, et al: Invasiveness and MMP expression in pancreatic carcinoma. J Surg Res 2001,98:33-39.
49. Koshiba T, Hosotani R, Wada M, et al. Involvement of matrix metalloproteinase-2 activity in invasion and metastasis of pancreatic carcinoma. Cancer, 1998, 82(4):642-650.
50. Byun HJ, Hong IK, Kim E, et al. A splice variant of CD99 increases motility and MMP-9 expression of human breast cancer cells through the AKT-, ERK-, and JNK-dependent AP-1 activation signaling pathways. J Biol Chem, 2006, 281(46):34833-34847.
51. Yu X, Lin SG, Huang XR, et al. Macrophage migration inhibitory factor induces MMP-9 expression in macrophages via the MEK-ERK MAP kinase pathway. J Interferon Cytokine Res, 2007, 27(2): 103-109.
52. Sun HW, Li CJ, Chen HQ, et al. Involvement of integrins, MAPK, and NF-kappaB in regulation of the shear stress-induced MMP-9 expression in endothelial cells. Biochem Biophys Res Commun, 2007,353(1):152-158.
53. Khanna C, Khan J, Nguyen P, et al. Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res,2001,61(9):3750-3759.
54. Stapleton G, Malliri A, Ozanne BW. Downregulated AP-1 activity is associated with inhibition of Protein-Kinase-C-dependent CD44 and ezrin localisation and upregulation of PKC theta in A431 cells. J Cell Sci, 2002, 115(Pt 13):2713-2724.
55. Crepaldi T, Gautreau A, Comoglio PM, et al. Ezrin is an effector of hepatocyte growth factor-mediated migration and morphogenesis in epithelial cells. J Cell Biol, 1997, 138(2):423-434.
56. Li Q, Wu MF, Song AP, et al. Expression of Ezrin and E-cadherin in invasive ductal breast cancer and their correlations to lymphatic metastasis. Ai Zheng, 2006, 25(3):363-366.
57. Guan XQ, Wang CJ, Li YY. Effects of Ezrin on differentiation and adhesion of hepatocellular carcinoma. Ai Zheng, 2002, 21(3):281-284.
58. Nestl A, Von Stein OD, Zatloukal K, et al. Gene expression patterns associated with the metastatic phenotype in rodent and human tumors.Cancer Res, 2001, 61(4):1569-1577.
59. Serrador JM, Nieto M, Alonso-Lebrero JL, et al. CD43 interacts with moesin and ezrin and regulates its redistribution to the uropods of T lymphocytes at the cell-cell contacts. Blood, 1998, 91(12):4632-4644.
60. Helander TS, Carpen O, Turunen O, et al. ICAM-2 redistributed by ezrin as a target for killer cells. Nature, 1996, 382(6588):265-268.
61. Poullet P, Gautreau A, Kadare G, et al. Ezrin interacts with focal adhesion kinase and induces its activation independently of cell-matrix adhesion. J Biol Chem, 2001, 276(40):37686-37691.
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63. Barros JC, Marshall CJ. Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton.J Cell Sci, 2005, 118(Pt8):1663-1671.
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