進階搜尋


下載電子全文  
系統識別號 U0026-1308201410224000
論文名稱(中文) SPAK在第三型鉀氯離子共同輸送體的訊息傳導途徑中的角色
論文名稱(英文) The role of SPAK in the potassium chloride cotransporter 3 (KCC3) signaling
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 102
學期 2
出版年 103
研究生(中文) 邱敏熙
研究生(英文) Min-Hsi Chiu
學號 s58941028
學位類別 博士
語文別 英文
論文頁數 68頁
口試委員 召集委員-沈孟儒
口試委員-劉校生
口試委員-鄭宏祺
指導教授-周振陽
口試委員-洪文俊
口試委員-施能耀
中文關鍵字 第三型鉀氯離子共同輸送體  SPAK  NFκB  MMP  腫瘤侵略性 
英文關鍵字 KCC3  SPAK  NFκB  MMP  tumor aggressiveness 
學科別分類
中文摘要 Ste20-related proline-alanine-rich kinase (SPAK) 參與多種細胞的功能,並且與第三型鉀氯離子共同輸送體 (Potassium chloride cotransporter 3, KCC3) 有相互作用; 然而SPAK相對於KCC3作用的重要性仍未被証明。在此篇論文中我們想要探討SPAK在KCC3所調控的細胞侵襲和腫瘤形成作用中所扮演的角色。我們指出引發KCC3表現過程會同時啟動NFκB的活化和SPAK訊息傳遞流程,進而導致p38 mitogen- activated protein kinase (MAPK) 和matrix metalloproteinase-2 (MMP2) 的活化和強化NFκB與位在SPAK promoter上NFκB可能結合位的結合作用,因此我們推論SPAK/ MMP2軸線是被NFκB所促進的。經由small interference RNA技術所媒介而造成SPAK 蛋白質的減少作用會抑制子宮頸癌細胞的細胞侵襲、致癌能力和在小鼠上異種移植腫瘤生成的作用。在經化學藥物抑制NFκB或MMP2的作用後,會抵銷KCC3-triggered, SPAK-dependent細胞侵襲作用。更進一步,p38 MAPK被証實為KCC3-dependent MMP2活化作用的上游調控者。我們總結推論SPAK可以經由調控NFκB/ p38 MAPK /MMP2 axis來促進KCC3所媒介之腫瘤侵略性作用。我們先前結果指出KCC3是能增強細胞增生和促進epithelial to mesenchymal transition (EMT)作用。在本論文中,我們分析人類子宮頸癌和卵巢癌細胞株,結果指出SPAK和EMT 標識蛋白表現間呈現正相關性。然而SPAK在促進EMT作用中所扮演的角色仍是不清楚。我們因此去測試SPAK在KCC3媒介的EMT現象所扮演的角色。我們分析比較SiHa和SiHaKCC3 細胞的形態觀察的表現,結果指出SiHa細胞在形態上表現出鱗狀細胞癌的特性: well- organized cell-cell association,SiHaKCC3則表現出類似間質細胞的特性:形成較長細胞形態和增加細胞分散性。經由一種small interference RNA技術造成降低SPAK蛋白表現,進而干擾降低細胞分散性和增加well-organized cell- cell associated。此外SPAK和EMT指標蛋白的immunoblotting和confocal immunofluorescent所得結果指出KCC3過度表現會顯著降低上皮細胞指標蛋白 (E-cadherin和β-catenin) 的表現、同時增加間質細胞指標蛋白 (vimentin) 表現。進一步利用small interference RNA 去降低SPAK表現,同時也會降低間質細胞指標蛋白 (vimentin) 表現但會增加上皮細胞指標蛋白 (E-cadherin和β-catenin) 表現。我們總結推論是SPAK具有促進KCC3-mediated EMT的能力.
英文摘要 Ste20-related proline-alanine-rich kinase (SPAK) plays a role in regulating many biological activities, and interacts with the K-Cl cotransporter (KCC) 3; however, the importance of SPAK for KCC3 function has not been demonstrated. Here, we investigated the role of SPAK in KCC3-regulated cell invasiveness and tumor formation. We show that the induction of KCC3 expression triggers the activation of the NFκB and SPAK signaling cascades, leading to the activation of p38 mitogen-activated protein kinase (MAPK) and matrix metalloproteinase-2 (MMP2) and augmented binding of NFκB to its putative SPAK promoter binding site, suggesting that the SPAK/MMP2 axis is up-regulated by NFκB. A small interference RNA-mediated reduction in SPAK protein levels suppressed the invasive ability and oncogenic potential of cervical cancer cells, and decreased tumor formation in mouse xenografts. Pharmacological inhibition of NFκB or MMP2 abrogated KCC3-triggered, SPAK-dependent cell invasiveness. Furthermore, p38 MAPK was identified as the upstream regulator of KCC3-dependent MMP2 activation. We concluded that SPAK may promote the KCC3-mediated tumor aggressiveness via the NFκB/p38 MAPK /MMP2 axis.
Our previous data explored KCC3 could enhance cell proliferation and promote epithelial to mesenchymal transition (EMT). Here, we indicate the SPAK and EMT have positive correlation human cervical and ovarian cancer lines. However, the role of SPAK in promoting EMT was unclear. We therefore examined whether the role of SPAK involved in KCC3-mediated EMT. Our data indicated that SiHa cells exhibited well-organized cell-cell association which is the characteristics of squamous cell carcinoma. SiHaKCC3 could dramatically induce the elongation of cell shape and increased scattering, similar to the morphology of mesenchymal cells. Furthermore, a small interference RNA-mediated reduction in SPAK protein levels suppressed the KCC3-mediated cell scattering effects but increase well-organized cell-cell associated and islet-like structure. Our data from immunoblotting and confocal immunofluorescent of EMT marker protein indicated KCC3 overexpression could dramatically decrease the expression of the epithelial marker (E-cadherin and β-catenin) and increase the expression of the mesenchymal marker (vimentin) compare to parental SiHa cells. In addition, KCC3 overexpression was accompanied by the increasing expression of SPAK. In contrast, a small interference RNA-mediated reduction in SPAK protein levels suppressed mesenchymal marker (vimentin) expression but increased epithelial marker (E-cadherin and β-catenin). We concluded that SPAK may promote the KCC3-mediated EMT.
論文目次 Table of contents
中文摘要………………………………………………………………………………..… I
Abstract…………………………………………………………………………………..III
致謝…….……………………………………………………………………...…………..V
Table of contents………………………………………………………………………....VI
Figure List………………………………………………………………………………....X
Abbreviations…………………………………………………………………………….XI
Chapter 1. Introduction……………………………………………………………….…..1
1. The potassium chloride cotransporters (KCCs) family………………………...…...1
1.1 The cation/Cl- cotransporter gene family (solute carrier family 12, SLC12)…...1
1.2 The K-Cl cotransporter (KCCs) family………………………………………...…1
1.3 Related functions and disorders of KCCs………………………………………...3
1.4 The roles of KCCs in tumor biology…………………………………………….....4
2. The Ste20-related proline-alanine-rich kinase (SPAK)……………………………...5
2.1 The STE20 family………………………………………...………………………....5
2.2 The Ste20-related proline-alanine-rich kinase (SPAK)……………………...…....5
2.3 Related functions and disorders of SPAK……………………………………........6
3. The relationship between SPAK and KCC3……………………………...………….7
4. Epithelial to mesenchymal transition (EMT)…………………………………..……7
4.1 Characterization of the EMT………………………………………………………7
4.2 The roles of KCCs in the EMT………………………………..…………………...8
4.3 The relationship between SPAK and EMT…………………………………...…..9
5. Objective and Specific aims….…………………………………………………...…..9
Chapter 2. Materials and Methods……………………………………………………...10
1. Cell culture, cell growth assay and reagents………………………………………..10
2. Transfection, establishment of stable cell lines and shRNA silencing………..…....11
3. Cell growth assay (MTT)…………………………………..………………………...11
4. Subcellular fraction protein collection……………………………………………....11
5. Western blotting assay…………………………………………………..…………...12
6. Co-immunoprecipitation assay…………………………………………………..….13
7. NFκB luciferase reporter assay………………………………………………….......13
8. Reverse transcription PCR and quantitative real-time RT-PCR………..………..13
9. Immunofluorescence staining (IF)…………………………..………………………15
10. Transwell invasion assay…………………………………...………………………...15
11. Gelatin zymography analysis……………………………………..…………………16
12. Chromatin immunoprecipitation assay (ChIP)……………………………….…....16
13. Anchorage-independent soft agar assay………………………………………….....16
14. Cell attachment assay……………………………….………………………………..17
15. Foci formation assay…………………………………………………………………17
16. Animal experiments……………………………………………………………….....17
17. Statistical analysis……………………………………………………...…………….18
Chapter 3. SPAK mediates KCC3-enhanced cervical cancer tumorogenesis…...……19
1. Induction of KCC3 expression is accompanied by increased SPAK expression....19
2. KCC3 increases the expression of SPAK and binding of SPAK to F-actin…….....20
3. KCC3 induces SPAK expression through binding of NFκB to the SPAK promoter………………………………………………………………………………20
4. KCC3-triggered, SPAK-dependent cell invasion occurs through the p38 MAPK /MMP2 axis….………………………………………..………………………………22
5. Silencing SPAK suppresses KCC3-mediated tumor formation……………..….....23
Chapter 4. SPAK modulate KCC3-mediated EMT effect……………………………..25
1. SPAK involved in the EMT………………………....……………………………….25
2. SPAK involved in KCC3-mediated EMT………………………………..…………26
3. SPAK shRNA reverse KCC3 -mediated EMT via Snai1..........................................26
4. Silencing SPAK suppresses KCC3-mediated In vitro invasion and colony formation activity………………………………………………………………….....27
Chapter 5. Discussion….…………………………………………………...…………….29
1. SPAK and cytoskeleton……………………………………………............................29
2. SPAK and NFκB …………………………………………………..............................30
3. SPAK, KCC3 and tumor biology...……………………………………….................30
4. SPAK mediates KCC3-enhanced cervical cancer tumorogenesis............................31
5. SPAK modulate KCC3-mediated EMT effect……...................................................32
6. Perspective……………………………………………………………………………33
Chapter 6. Conclusion………………………………...………………………….………35
Chapter 7. References….……………………………………………………..………….36
Table………………………………………………………………..……………………..46
Figures…………………………………………………………………………..………...47












Figure List
Figure 1. Induction of KCC3 expression is accompanied by increased SPAK expression in SiHa cells……………………………………………………………….47
Figure 2. Induction of KCC3 expression is accompanied by increased SPAK expression in HeLa cells……………………………………………………………....49
Figure 3. KCC3 increases the expression of SPAK and binding of SPAK to F-actin...52
Figure 4. KCC3 induces SPAK expression through binding of NFκB to the SPAK promoter……………………………………………………………………….............54
Figure 5. The KCC3-triggered, SPAK-dependent, cell invasion ability occurs through the p38 MAPK /MMP2 axis…………………………………………………………..57
Figure 6. Silencing SPAK suppresses KCC3-mediated tumor formation……...……..60
Figure 7. Effect of SPAK on EMT marker protein expression and morphological change in human cervical cancer and ovarian cancer……………………...…..…..62
Figure 8. SPAK shRNA reverse KCC3 overexpression induce EMT effect via Snai1.64
Figure 9. Silencing SPAK suppresses KCC3-mediated In vitro invasion and colony formation activity…………………………………………………………...………...67
Figure 10. Schematic presentation of the putative mechanisms for the regulation of KCC3-mediated tumor aggressiveness……………………………………………....68
參考文獻 1. Piechotta, K., Lu, J., and Delpire, E. (2002) Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1). J Biol Chem 277, 50812-50819
2. Piechotta, K., Garbarini, N., England, R., and Delpire, E. (2003) Characterization of the interaction of the stress kinase SPAK with the Na+-K+-2Cl- cotransporter in the nervous system: evidence for a scaffolding role of the kinase. J Biol Chem 278, 52848-52856
3. Lauf, P. K. (1982) Evidence for chloride-dependent potassium and water transport induced by hyposmotic stress in erythrocytes of the marine teleost, opsanus tau. J Comp Physiol 146, 9-16
4. Dunham, P. B., Ellory, J.C. (1981) Passive transport in low potassium sheep red cells: dependence on cell volume and chloride. J Physiol (Lond) 318, 511-530
5. Mercado, A., Song, L., Vazquez, N., Mount, D. B., and Gamba, G. (2000) Functional comparison of the K+-Cl- cotransporters KCC1 and KCC4. J Biol Chem 275, 30326-30334
6. Rinehart, J., Maksimova, Y. D., Tanis, J. E., Stone, K. L., Hodson, C. A., Zhang, J., Risinger, M., Pan, W., Wu, D., Colangelo, C. M., Forbush, B., Joiner, C. H., Gulcicek, E. E., Gallagher, P. G., and Lifton, R. P. (2009) Sites of regulated phosphorylation that control K-Cl cotransporter activity. Cell 138, 525-536
7. Gillen, C. M., Brill, S., Payne, J. A., and Forbush, B., 3rd. (1996) Molecular cloning and functional expression of the K-Cl cotransporter from rabbit, rat, and human. A new member of the cation-chloride cotransporter family. J Biol Chem 271, 16237-16244
8. Payne, J. A., Stevenson, T. J., and Donaldson, L. F. (1996) Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform. J Biol Chem 271, 16245-16252
9. Mount, D. B., Mercado, A., Song, L., Xu, J., George, A. L., Jr., Delpire, E., and Gamba, G. (1999) Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family. J Biol Chem 274, 16355-16362
10. Race, J. E., Makhlouf, F. N., Logue, P. J., Wilson, F. H., Dunham, P. B., and Holtzman, E. J. (1999) Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter. Am J Physiol Cell Physiol 277, C1210-1219
11. Hiki, K., D'Andrea, R. J., Furze, J., Crawford, J., Woollatt, E., Sutherland, G. R., Vadas, M. A., and Gamble, J. R. (1999) Cloning, characterization, and chromosomal location of a novel human K+-Cl- cotransporter. J Biol Chem 274, 10661-10667
12. Wei, W. C., Akerman, C. J., Newey, S. E., Pan, J., Clinch, N. W., Jacob, Y., Shen, M. R., Wilkins, R. J., and Ellory, J. C. (2011) The potassium-chloride cotransporter 2 promotes cervical cancer cell migration and invasion by an ion transport-independent mechanism. J Physiol (London) 589, 5349-5359
13. Bellemer, A., Hirata, T., Romero, M. F., and Koelle, M. R. (2011) Two types of chloride transporters are required for GABA(A) receptor-mediated inhibition in C. elegans. EMBO J 30, 1852-1863
14. Hekmat-Scafe, D. S., Lundy, M. Y., Ranga, R., and Tanouye, M. A. (2006) Mutations in the K+/Cl- cotransporter gene kazachoc (kcc) increase seizure susceptibility in Drosophila. J Neurosci 26, 8943-8954
15. Capo-Aponte, J. E., Wang, Z., Akinci, M. A., Wolosin, J. M., Pokorny, K. S., Iserovish, P., and Reinach, P. S. (2007) Potassium-chloride cotransporter mediates cell cycle progression and proliferation of human corneal epithelial cells. Cell Cycle 6, 2709-2718
16. Kajiya, H., Okamoto, F., Li, J. P., Nakao, A., and Okabe, K. (2006) Expression of mouse osteoclast K-Cl Co-transporter-1 and its role during bone resorption. J Bone Miner Res 21, 984-992
17. Kakazu, Y., Akaike, N., Komiyama, S., and Nabekura, J. (1999) Regulation of intracellular chloride by cotransporters in developing lateral superior olive neurons. J Neurosci 19, 2843-2851
18. Shen, M. R., Chou, C. Y., Hsu, K. F., Liu, H. S., Dunham, P. B., Holtzman, E. J., and Ellory, J. C. (2001) The KCl cotransporter isoform KCC3 can play an important role in cell growth regulation. Proc Natl Acad Sci USA 98, 14714-14719
19. Benarroch, E. E. (2013) Cation-chloride cotransporters in the nervous system: general features and clinical correlations. Neurology 80, 756-763
20. Hsu, Y. M., Chen, Y. F., Chou, C. Y., Tang, M. J., Chen, J. H., Wilkins, R. J., Ellory, J. C., and Shen, M. R. (2007) KCl cotransporter-3 down-regulates E-cadherin/beta-catenin complex to promote epithelial-mesenchymal transition. Cancer Res 67, 11064-11073
21. Sun, Y. T., Shieh, C. C., Delpire, E., and Shen, M. R. (2012) K(+)-Cl(-) cotransport mediates the bactericidal activity of neutrophils by regulating NADPH oxidase activation. J Physiol (London) 590, 3231-3243
22. Fujii, T., Takahashi, Y., Itomi, Y., Fujita, K., Morii, M., Tabuchi, Y., Asano, S., Tsukada, K., Takeguchi, N., and Sakai, H. (2008) K+-Cl- Cotransporter-3a Up-regulates Na+,K+-ATPase in Lipid Rafts of Gastric Luminal Parietal Cells. J Biol Chem 283, 6869-6877
23. Hsu, Y. M., Chou, C. Y., Chen, H. H., Lee, W. Y., Chen, Y. F., Lin, P. W., Alper, S. L., Ellory, J. C., and Shen, M. R. (2007) IGF-1 upregulates electroneutral K-Cl cotransporter KCC3 and KCC4 which are differentially required for breast cancer cell proliferation and invasiveness. J Cell Physiol 210, 626-636
24. Fujii, T., Takahashi, Y., Ikari, A., Morii, M., Tabuchi, Y., Tsukada, K., Takeguchi, N., and Sakai, H. (2009) Functional association between K+-Cl- cotransporter-4 and H+,K+-ATPase in the apical canalicular membrane of gastric parietal cells. J Biol Chem 284, 619-629
25. Hubner, C. A., and Jentsch, T. J. (2002) Ion channel diseases. Hum Mol Genet 11, 2435-2445
26. Bize, I. (2001) Theoretical validation for a model of KCC regulation in human erythrocytes. Blood Cell Mol Dis 27, 121-126
27. Palma, E., Amici, M., Sobrero, F., Spinelli, G., Di Angelantonio, S., Ragozzino, D., Mascia, A., Scoppetta, C., Esposito, V., Miledi, R., and Eusebi, F. (2006) Anomalous levels of Cl- transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory. Proc Natl Acad Sci USA 103, 8465-8468
28. Boettger, T., Rust, M. B., Maier, H., Seidenbecher, T., Schweizer, M., Keating, D. J., Faulhaber, J., Ehmke, H., Pfeffer, C., Scheel, O., Lemcke, B., Horst, J., Leuwer, R., Pape, H. C., Volkl, H., Hubner, C. A., and Jentsch, T. J. (2003) Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J 22, 5422-5434
29. Howard, H. C., Mount, D. B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J. B., Prevost, C., Horst, J., Simonati, A., Lemcke, B., Welch, R., England, R., Zhan, F. Q., Mercado, A., Siesser, W. B., George, A. L., Jr., McDonald, M. P., Bouchard, J. P., Mathieu, J., Delpire, E., and Rouleau, G. A. (2002) The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nature Genet 32, 384-392
30. Shen, M. R., Chou, C. Y., and Ellory, J. C. (2000) Volume-sensitive KCI cotransport associated with human cervical carcinogenesis. Pflugers Arch 440, 751-760
31. Shen, M. R., Chou, C. Y., Hsu, K. F., Hsu, Y. M., Chiu, W. T., Tang, M. J., Alper, S. L., and Ellory, J. C. (2003) KCl cotransport is an important modulator of human cervical cancer growth and invasion. J Biol Chem 278, 39941-39950
32. Shen, M. R., Lin, A. C., Hsu, Y. M., Chang, T. J., Tang, M. J., Alper, S. L., Ellory, J. C., and Chou, C. Y. (2004) Insulin-like growth factor 1 stimulates KCl cotransport, which is necessary for invasion and proliferation of cervical cancer and ovarian cancer cells. J Biol Chem 279, 40017-40025
33. Chen, Y. F., Chou, C. Y., Wilkins, R. J., Ellory, J. C., Mount, D. B., and Shen, M. R. (2009) Motor protein-dependent membrane trafficking of KCl cotransporter-4 is important for cancer cell invasion. Cancer Res 69, 8585-8593
34. Strange, K., Denton, J., and Nehrke, K. (2006) Ste20-type kinases: evolutionarily conserved regulators of ion transport and cell volume. Physiology (Bethesda) 21, 61-68
35. Johnston, A. M., Naselli, G., Gonez, L. J., Martin, R. M., Harrison, L. C., and DeAizpurua, H. J. (2000) SPAK, a STE20/SPS1-related kinase that activates the p38 pathway. Oncogene 19, 4290-4297
36. Gagnon, K. B., and Delpire, E. (2012) Molecular physiology of SPAK and OSR1: two Ste20-related protein kinases regulating ion transport. Physiol Rev 92, 1577-1617
37. Yan, Y., Nguyen, H., Dalmasso, G., Sitaraman, S. V., and Merlin, D. (2007) Cloning and characterization of a new intestinal inflammation-associated colonic epithelial Ste20-related protein kinase isoform. Biochim Biophys Acta 1769, 106-116
38. Dan, I., Watanabe, N. M., and Kusumi, A. (2001) The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol 11, 220-230
39. Delpire, E., and Gagnon, K. B. (2006) SPAK and OSR1, key kinases involved in the regulation of chloride transport. Acta Physiol 187, 103-113
40. Li, Y., Hu, J., Vita, R., Sun, B., Tabata, H., and Altman, A. (2004) SPAK kinase is a substrate and target of PKCtheta in T-cell receptor-induced AP-1 activation pathway. EMBO J 23, 1112-1122
41. Tsutsumi, T., Ushiro, H., Kosaka, T., Kayahara, T., and Nakano, K. (2000) Proline- and alanine-rich Ste20-related kinase associates with F-actin and translocates from the cytosol to cytoskeleton upon cellular stresses. J Biol Chem 275, 9157-9162
42. Delpire, E., and Gagnon, K. B. (2008) SPAK and OSR1: STE20 kinases involved in the regulation of ion homoeostasis and volume control in mammalian cells. J Biol Chem 409, 321-331
43. Yang, L., Cai, X., Zhou, J., Chen, S., Chen, Y., Chen, Z., Wang, Q., Fang, Z., and Zhou, L. (2013) STE20/SPS1-related proline/alanine-rich kinase is involved in plasticity of GABA signaling function in a mouse model of acquired epilepsy. PloS one 8, e74614
44. Glover, M., and O'Shaughnessy K, M. (2011) SPAK and WNK kinases: a new target for blood pressure treatment? Curr Opin Nephrol Hypertens 20, 16-22
45. Yan, Y., Laroui, H., Ingersoll, S. A., Ayyadurai, S., Charania, M., Yang, S., Dalmasso, G., Obertone, T. S., Nguyen, H., Sitaraman, S. V., and Merlin, D. (2011) Overexpression of Ste20-related proline/alanine-rich kinase exacerbates experimental colitis in mice. J Immunol 187, 1496-1505
46. de Los Heros, P., Alessi, D. R., Gourlay, R., Campbell, D. G., Deak, M., Macartney, T. J., Kahle, K. T., and Zhang, J. (2014) The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. Biochem J 458, 559-573
47. Delpire, E., and Gagnon, K. B. (2007) Genome-wide analysis of SPAK/OSR1 binding motifs. Physiol Genomics 28, 223-231
48. Casula, S., Shmukler, B. E., Wilhelm, S., Stuart-Tilley, A. K., Su, W., Chernova, M. N., Brugnara, C., and Alper, S. L. (2001) A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity. J Biol Chem 276, 41870-41878
49. Wu, S. Y., Lan, S. H., Cheng, D. E., Chen, W. K., Shen, C. H., Lee, Y. R., Zuchini, R., and Liu, H. S. (2011) Ras-related tumorigenesis is suppressed by BNIP3-mediated autophagy through inhibition of cell proliferation. Neoplasia 13, 1171-1182
50. Yamani, M. H., Tuzcu, E. M., Starling, R. C., Ratliff, N. B., Yu, Y., Vince, D. G., Powell, K., Cook, D., McCarthy, P., and Young, J. B. (2002) Myocardial ischemic injury after heart transplantation is associated with upregulation of vitronectin receptor (alpha(v)beta3), activation of the matrix metalloproteinase induction system, and subsequent development of coronary vasculopathy. Circulation 105, 1955-1961
51. Yan, Y., Dalmasso, G., Nguyen, H. T., Obertone, T. S., Charrier-Hisamuddin, L., Sitaraman, S. V., and Merlin, D. (2008) Nuclear factor-kappaB is a critical mediator of Ste20-like proline-/alanine-rich kinase regulation in intestinal inflammation. Am J Pathol 173, 1013-1028
52. Posadas, I., Santos, P., and Cena, V. (2012) Acetaminophen induces human neuroblastoma cell death through NFKB activation. PloS one 7, e50160
53. Hadler-Olsen, E., Winberg, J. O., and Uhlin-Hansen, L. (2013) Matrix metalloproteinases in cancer: their value as diagnostic and prognostic markers and therapeutic targets. Tumour Biol 34, 2041-2051
54. Vasaturo, F., Solai, F., Malacrino, C., Nardo, T., Vincenzi, B., Modesti, M., and Scarpa, S. (2013) Plasma levels of matrix metalloproteinases 2 and 9 correlate with histological grade in breast cancer patients. Oncol Lett 5, 316-320
55. Hou, X., Han, Q. H., Hu, D., Tian, L., Guo, C. M., Du, H. J., Zhang, P., Wang, Y. S., and Hui, Y. N. (2009) Mechanical force enhances MMP-2 activation via p38 signaling pathway in human retinal pigment epithelial cells. Clin Exp Ophthalmol 247, 1477-1486
56. Kwon, C. H., Moon, H. J., Park, H. J., Choi, J. H., and Park do, Y. (2013) S100A8 and S100A9 promotes invasion and migration through p38 mitogen-activated protein kinase-dependent NF-kappaB activation in gastric cancer cells. Mol cells 35, 226-234
57. Denkert, C., Siegert, A., Leclere, A., Turzynski, A., and Hauptmann, S. (2002) An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. Clin Exp Metastasis 19, 79-85
58. Ma, W. L., Jeng, L. B., Lai, H. C., Liao, P. Y., and Chang, C. (2014) Androgen receptor enhances cell adhesion and decreases cell migration via modulating beta1-integrin-AKT signaling in hepatocellular carcinoma cells. Cancer lett 351, 64-71
59. Wang, X., Ji, X., Chen, J., Yan, D., Zhang, Z., Wang, Q., Xi, X., and Feng, Y. (2014) SOX2 Enhances the Migration and Invasion of Ovarian Cancer Cells via Src Kinase. PloS one 9, e99594
60. Tsutsumi, T., Kosaka, T., Ushiro, H., Kimura, K., Honda, T., Kayahara, T., and Mizoguchi, A. (2008) PASK (proline-alanine-rich Ste20-related kinase) binds to tubulin and microtubules and is involved in microtubule stabilization. Arch Biochem Biophys 477, 267-278
61. DiDonato, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E., and Karin, M. (1997) A cytokine-responsive IkappaB kinase that activates the transcription factor NF-kappaB. Nature 388, 548-554
62. Senftleben, U., Cao, Y., Xiao, G., Greten, F. R., Krahn, G., Bonizzi, G., Chen, Y., Hu, Y., Fong, A., Sun, S. C., and Karin, M. (2001) Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293, 1495-1499
63. Li, Z. L., Shao, S. H., Xie, S. Y., Yue, Z., and Ma, Y. (2011) Anti-sense nucleic acid of CyclinD1 induces apoptosis of lung adenocarcinoma cancer cell A549. Acta physiol Sin 63, 261-266
64. Dong, W., Li, H., Zhang, Y., Yang, H., Guo, M., Li, L., and Liu, T. (2011) Matrix metalloproteinase 2 promotes cell growth and invasion in colorectal cancer. Acta Biochim Biophys Sin 43, 840-848
65. Zhao, Y., Yang, Z. Q., Wang, Y., Miao, Y., Liu, Y., Dai, S. D., Han, Y., and Wang, E. H. (2010) Dishevelled-1 and dishevelled-3 affect cell invasion mainly through canonical and noncanonical Wnt pathway, respectively, and associate with poor prognosis in nonsmall cell lung cancer. Mol Carcinog 49, 760-770
66. Sun, H. Q., Yamamoto, M., Mejillano, M., and Yin, H. L. (1999) Gelsolin, a multifunctional actin regulatory protein. J Biol Chem 274, 33179-33182
67. Silacci, P., Mazzolai, L., Gauci, C., Stergiopulos, N., Yin, H. L., and Hayoz, D. (2004) Gelsolin superfamily proteins: key regulators of cellular functions. Cell Mol Llife Sci 61, 2614-2623
68. Tanaka, H., Shirkoohi, R., Nakagawa, K., Qiao, H., Fujita, H., Okada, F., Hamada, J., Kuzumaki, S., Takimoto, M., and Kuzumaki, N. (2006) siRNA gelsolin knockdown induces epithelial-mesenchymal transition with a cadherin switch in human mammary epithelial cells. Int J Cancer. 118, 1680-1691
69. Rahman, M., Miyamoto, H., and Chang, C. (2004) Androgen receptor coregulators in prostate cancer: mechanisms and clinical implications. Clin Cancer Res 10, 2208-2219
70. Mielnicki, L. M., Ying, A. M., Head, K. L., Asch, H. L., and Asch, B. B. (1999) Epigenetic regulation of gelsolin expression in human breast cancer cells. Exp Cell Res 249, 161-176
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2014-09-03起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2014-09-03起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw