進階搜尋


下載電子全文  
系統識別號 U0026-1408201420364800
論文名稱(中文) 利用去整合蛋白抑制肝癌細胞黏附、遷移及侵犯能力
論文名稱(英文) Inhibition of integrin-mediated adhesion, migration and invasion of hepatoma cells by disintegrins
校院名稱 成功大學
系所名稱(中) 醫學檢驗生物技術學系
系所名稱(英) Department of Medical Laboratory Science and Biotechnology
學年度 102
學期 2
出版年 103
研究生(中文) 林庚酉
研究生(英文) Kengyu Lin
學號 t36011078
學位類別 碩士
語文別 中文
論文頁數 73頁
口試委員 指導教授-黃溫雅
共同指導教授-莊偉哲
召集委員-顏家瑞
口試委員-王慧菁
中文關鍵字 肝癌  轉移  整合蛋白  去整合蛋白  B型肝炎x蛋白 
英文關鍵字 Hepatocellular carcinoma  metastasis  integrin  disintegrin  HBx 
學科別分類
中文摘要 肝臟是富含微血管的器官,當肝臟出現癌化時,癌細胞容易侵犯血管並且轉移,這使得肝癌患者治療後出現復發的機會增加。研究顯示,肝癌細胞藉由大量表現整合蛋白(integrin),促進細胞轉移、生長及血管新生的癌化作用。整合蛋白是由α及β次單元所形成的穿膜蛋白,它們負責調節細胞間、細胞與細胞外基質的交互作用。肝癌組織中發現,表現αv和β1相關的整合蛋白與癌症惡化有關,這類的整合蛋白可辨識RGD (arginine-glycine-aspartate)氨基酸序列結構,與細胞外基質黏附,誘發胞內外訊息傳遞。臨床實驗發現,抑制整合蛋白所調控的細胞活性可有效抑制癌化作用,而在肝病變的研究也指出,抑制αv和β1相關的整合蛋白可達到三點效果:第一,抑制整合蛋白調控的肝癌細胞黏附、遷移及侵犯能力;第二,抑制整合蛋白αv調控的肝纖維化;第三,抑制整合蛋白αvβ3、αvβ5及α5β1調控的血管新生。在本實驗中,我們試圖針對肝癌細胞表現的整合蛋白,抑制其生理活動。我們使用實驗室所開發的去整合蛋白(disintegrin) Rho、KG、KG-P和ARLDDL抑制肝癌細胞表現的整合蛋白。去整合蛋白源自於蛇毒蛋白,是天然的整合蛋白抑制劑,抑制強度為細胞外基質的1000倍以上,去整合蛋白含有RGD序列結構,利用此結構可與細胞外基質競爭整合蛋白的交互作用。目前已證實,去整合蛋白可抑制黑色素瘤的轉移及生長,同時也減緩腫瘤的血管新生。本實驗顯示,藉由去整合蛋白KG及KG-P針對整合蛋白αvβ3、αvβ5及α5β1,能有效抑制肝癌細胞對於細胞外基質(fibronectin、vitronectin)的黏附能力,其50%抑制濃度(IC50)介於15到80 nM;同時也具有抑制肝癌細胞遷移及侵犯能力,其IC50介於2到400 nM之間;然而單純針對整合蛋白αvβ3的ARLDDL則是較差的抑制效果。這些去整合蛋白對於肝癌細胞活性不具影響力。另外當肝癌細胞表現B型肝炎x蛋白(HBx)時,整合蛋白αvβ3及α5β1的表現量下降1.5倍以及3倍,同時減弱細胞的黏附能力並且增強細胞遷移及侵犯的趨勢,而這使得去整合蛋白無法有效抑制HBx蛋白誘發的細胞遷移能力。本篇證實整合蛋白αvβ3、αvβ5及α5β1參與肝癌細胞黏附、遷移及侵犯能力,且運用去整合蛋白可抑制肝癌細胞中整合蛋白調控的轉移能力,此結論可作為未來發展抑制肝癌轉移的藥物基礎。
英文摘要 Hepatocellular carcinoma (HCC) is a vascularized tumor. The prognosis of HCC is poor due to blood vessel invasion. Integrins are major receptors mediating cancer cell motility, proliferation and angiogenesis which make them appealing for cancer treatments. Previous studies show that integrin α5β1 antagonists can inhibit VEGF-induced angiogenesis in hepatocellular carcinoma, and hepatitis B virus x protein (HBx) can modulate integrin signaling pathways in hepatoma cells. In this study, we evaluated integrin expression levels of liver cell lines, the regulation of HBx proteins in integrin-mediated cellular functions, and the biological functions of integrins on cell adhesion, migration, invasion, and proliferation. We also used integrin antagonists, mono-specific (αvβ3) and multi-specific (αvβx and α5β1) disintegrins, to inhibit integrin-related cellular functions. We found the HBx-expressing hepatoma cells with the down-regulation of integrins α5β1 and αvβ3 expression which led to the decreases in hepatoma cell adhesion to fibronectin and vitronectin, as well as the increases in hepatoma cell migration and invasion. In conclusion, our study demonstrates that integrins participate in hepatoma cell adhesion, migration, and invasion. These cellular processes can be impaired by integrins-specific disintegrins. The results of this study serve as the basis to develop the potent integrin-specific drugs for the treatment of hepatocellular carcinoma.
論文目次 目錄
摘要 I
英文延伸摘要 III
誌謝 X
目錄 XI
表目錄 XIII
圖目錄 XIV
附錄圖目錄 XV
縮寫檢索表 XVI
第一章 緒論 1
1-1肝癌(Hepatocellular carcinoma) 1
1-2肝癌的治療 2
1-3整合蛋白(Integrin) 2
1-4整合蛋白與肝癌 4
1-5去整合蛋白(Disintegrin) 5
第二章 研究目標 7
第三章 材料與方法 8
3-1 抗體、蛋白與細胞株 8
3-1-1實驗用菌株、質體和培養液配方 8
3-1-2重組蛋白的表現與純化 10
3-2細胞株及培養方法 15
3-3流式細胞儀 16
3-4細胞黏附能力之研究 18
3-5去整合蛋白抑制細胞黏附能力之研究 19
3-6細胞遷移及侵犯能力之研究 19
3-7去整合蛋白抑制細胞遷移及侵犯能力之研究 20
3-8去整合蛋白抑制細胞存活能力之研究 20
3-9統計分析 21
第四章 結果 22
4-1肝癌細胞與肝臟星狀細胞的整合蛋白表現 22
4-2整合蛋白在肝癌細胞黏附能力所扮演的角色 22
4-3整合蛋白在肝癌細胞遷移及侵犯能力所扮演的角色 23
4-4去整合蛋白抑制肝癌細胞黏附能力 24
4-5去整合蛋白抑制肝癌細胞及肝臟星狀細胞遷移能力 25
4-6去整合蛋白抑制肝癌細胞侵犯能力 25
4-7去整合蛋白抑制肝癌細胞與肝臟星狀細胞存活能力 26
第五章 討論 27
5-1去整合蛋白抑制肝癌細胞中整合蛋白α5β1、αvβ3和αvβ5調控的細胞黏附、遷移及侵犯能力 27
5-2肝癌細胞表現B型肝炎病毒x蛋白時,整合蛋白α5β1和αvβ3表現量下降、細胞黏附能力下降,而細胞遷移和侵犯能力上升 29
5-3肝癌細胞表現的整合蛋白與細胞黏附、遷移及侵犯能力關聯性 30
第六章 結論 31
參考文獻 33
附表 40
附圖 46
附錄圖 62
參考文獻 1. Arnaout, M.A., Mahalingam, B., and Xiong, J.P. (2005). Integrin structure, allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 21, 381-410.
2. Au, L.C., Huang, Y.B., Huang, T.F., Teh, G.W., Lin, H.H., and Choo, K.B. (1991). A common precursor for a putative hemorrhagic protein and rhodostomin, a platelet aggregation inhibitor of the venom of Calloselasma rhodostoma: molecular cloning and sequence analysis. Biochemical and biophysical research communications 181, 585-593.
3. Aucejo, F., Hanouneh, I., and Carey, W.D. (2013). Hepatocellular Carcinoma (The Cleveland Clinic Foundation).
4. Bandyopadhyay, A., and Raghavan, S. (2009). Defining the role of integrin alphavbeta6 in cancer. Current drug targets 10, 645-652.
5. Barczyk, M., Carracedo, S., and Gullberg, D. (2010). Integrins. Cell and tissue research 339, 269-280.
6. Bishayee, A., and Darvesh, A.S. (2012). Angiogenesis in hepatocellular carcinoma: a potential target for chemoprevention and therapy. Current cancer drug targets 12, 1095-1118.
7. Bochen, A., Marelli, U.K., Otto, E., Pallarola, D., Mas-Moruno, C., Di Leva, F.S., Boehm, H., Spatz, J.P., Novellino, E., Kessler, H., et al. (2013). Biselectivity of isoDGR peptides for fibronectin binding integrin subtypes alpha5beta1 and alphavbeta6: conformational control through flanking amino acids. Journal of medicinal chemistry 56, 1509-1519.
8. Boige, V., Malka, D., Bourredjem, A., Dromain, C., Baey, C., Jacques, N., Pignon, J.P., Vimond, N., Bouvet-Forteau, N., De Baere, T., et al. (2012). Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. The oncologist 17, 1063-1072.
9. Bouchard, M.J., and Schneider, R.J. (2004). The enigmatic X gene of hepatitis B virus. Journal of virology 78, 12725-12734.
10. Bouchard, M.J., Wang, L., and Schneider, R.J. (2006). Activation of focal adhesion kinase by hepatitis B virus HBx protein: multiple functions in viral replication. Journal of virology 80, 4406-4414.
11. Calvete, J.J., Marcinkiewicz, C., Monleon, D., Esteve, V., Celda, B., Juarez, P., and Sanz, L. (2005). Snake venom disintegrins: evolution of structure and function. Toxicon : official journal of the International Society on Toxinology 45, 1063-1074.
12. Chan, P.-T. (2012). Development of Integrins αvβx and α5β1-specific Antagonists Using Rhodostomin as a Scaffold. In Department of Biochemistry and Molecular Biology (National Cheng Kung University).
13. Chaparro, M., Gonzalez Moreno, L., Trapero-Marugan, M., Medina, J., and Moreno-Otero, R. (2008). Review article: pharmacological therapy for hepatocellular carcinoma with sorafenib and other oral agents. Alimentary pharmacology & therapeutics 28, 1269-1277.
14. Chen, C.-H. (2010). The Roles of Rhodostomin Mutants with an RXD Motif in Integrins Recognition and Anti-melanoma Tumor Cell Activity. In Department of Biochemistry and Molecular Biology (National Cheng Kung University).
15. Chen, Y.C., Cheng, C.H., Shiu, J.H., Chang, Y.T., Chang, Y.S., Huang, C.H., Lee, J.C., and Chuang, W.J. (2012). Expression in Pichia pastoris and characterization of echistatin, an RGD-containing short disintegrin. Toxicon : official journal of the International Society on Toxinology 60, 1342-1348.
16. Cheng, C.H., Chen, Y.C., Shiu, J.H., Chang, Y.T., Chang, Y.S., Huang, C.H., Chen, C.Y., and Chuang, W.J. (2012). Dynamics and functional differences between dendroaspin and rhodostomin: insights into protein scaffolds in integrin recognition. Protein science : a publication of the Protein Society 21, 1872-1884.
17. Chung, T.W., Lee, Y.C., and Kim, C.H. (2004). Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18, 1123-1125.
18. Desgrosellier, J.S., and Cheresh, D.A. (2010). Integrins in cancer: biological implications and therapeutic opportunities. Nature reviews Cancer 10, 9-22.
19. Feitelson, M.A., Reis, H.M., Tufan, N.L., Sun, B., Pan, J., and Lian, Z. (2009). Putative roles of hepatitis B x antigen in the pathogenesis of chronic liver disease. Cancer letters 286, 69-79.
20. Fransvea, E., Mazzocca, A., Antonaci, S., and Giannelli, G. (2009). Targeting transforming growth factor (TGF)-betaRI inhibits activation of beta1 integrin and blocks vascular invasion in hepatocellular carcinoma. Hepatology (Baltimore, Md) 49, 839-850.
21. Geng, Z.M., Jha, R.K., Li, B., Chen, C., Li, W.Z., Zheng, J.B., Wang, L., and Huanchen, S. (2014). Sorafenib Inhibition of Hepatic Stellate Cell Proliferation in Tumor Microenvironment of Hepatocellular Carcinoma: A Study of the Sorafenib Mechanisms. Cell biochemistry and biophysics.
22. Giancotti, F.G., and Tarone, G. (2003). Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annual review of cell and developmental biology 19, 173-206.
23. Giannelli, G., Bergamini, C., Fransvea, E., Marinosci, F., Quaranta, V., and Antonaci, S. (2001). Human hepatocellular carcinoma (HCC) cells require both alpha3beta1 integrin and matrix metalloproteinases activity for migration and invasion. Laboratory investigation; a journal of technical methods and pathology 81, 613-627.
24. Goodman, S.L., and Picard, M. (2012). Integrins as therapeutic targets. Trends in pharmacological sciences 33, 405-412.
25. Gould, R.J., Polokoff, M.A., Friedman, P.A., Huang, T.F., Holt, J.C., Cook, J.J., and Niewiarowski, S. (1990). Disintegrins: a family of integrin inhibitory proteins from viper venoms. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine (New York, NY) 195, 168-171.
26. Guo, R.T., Chou, L.J., Chen, Y.C., Chen, C.Y., Pari, K., Jen, C.J., Lo, S.J., Huang, S.L., Lee, C.Y., Chang, T.W., et al. (2001). Expression in Pichia pastoris and characterization by circular dichroism and NMR of rhodostomin. Proteins 43, 499-508.
27. Henderson, N.C., Arnold, T.D., Katamura, Y., Giacomini, M.M., Rodriguez, J.D., McCarty, J.H., Pellicoro, A., Raschperger, E., Betsholtz, C., Ruminski, P.G., et al. (2013). Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nature medicine 19, 1617-1624.
28. Huang, C.-H. (2014).
29. Huang, T.F., Wu, Y.J., and Ouyang, C. (1987). Characterization of a potent platelet aggregation inhibitor from Agkistrodon rhodostoma snake venom. Biochimica et biophysica acta 925, 248-257.
30. Jaskiewicz, K., Chasen, M.R., and Robson, S.C. (1993). Differential expression of extracellular matrix proteins and integrins in hepatocellular carcinoma and chronic liver disease. Anticancer research 13, 2229-2237.
31. Jung, C.W., Song, T.J., Lee, K.O., Choi, S.B., Kim, W.B., Suh, S.O., Kim, Y.C., and Choi, S.Y. (2012). Characterization of hepatocellular carcinoma cell lines based on cell adhesion molecules. International journal of molecular medicine 29, 1158-1164.
32. Kane, R.C., Farrell, A.T., Madabushi, R., Booth, B., Chattopadhyay, S., Sridhara, R., Justice, R., and Pazdur, R. (2009). Sorafenib for the treatment of unresectable hepatocellular carcinoma. The oncologist 14, 95-100.
33. Lara-Pezzi, E., Gomez-Gaviro, M.V., Galvez, B.G., Mira, E., Iniguez, M.A., Fresno, M., Martinez, A.C., Arroyo, A.G., and Lopez-Cabrera, M. (2002). The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression. The Journal of clinical investigation 110, 1831-1838.
34. Lara-Pezzi, E., Majano, P.L., Yanez-Mo, M., Gomez-Gonzalo, M., Carretero, M., Moreno-Otero, R., Sanchez-Madrid, F., and Lopez-Cabrera, M. (2001). Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix. Journal of hepatology 34, 409-415.
35. Laurens, N., Engelse, M.A., Jungerius, C., Lowik, C.W., van Hinsbergh, V.W., and Koolwijk, P. (2009). Single and combined effects of alphavbeta3- and alpha5beta1-integrins on capillary tube formation in a human fibrinous matrix. Angiogenesis 12, 275-285.
36. Lin, K.T., Yeh, S.H., Chen, D.S., Chen, P.J., and Jou, Y.S. (2005). Epigenetic activation of alpha4, beta2 and beta6 integrins involved in cell migration in trichostatin A-treated Hep3B cells. Journal of biomedical science 12, 803-813.
37. Lin, N., Chen, Z., Lu, Y., Li, Y., Hu, K., and Xu, R. (2014). Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma. Hepatology research : the official journal of the Japan Society of Hepatology.
38. Liu, L.P., Liang, H.F., Chen, X.P., Zhang, W.G., Yang, S.L., Xu, T., and Ren, L. (2010). The role of NF-kappaB in Hepatitis b virus X protein-mediated upregulation of VEGF and MMPs. Cancer investigation 28, 443-451.
39. Maor, Y., and Malnick, S. (2013). Liver injury induced by anticancer chemotherapy and radiation therapy. International journal of hepatology 2013, 815105.
40. Mas-Moruno, C., Rechenmacher, F., and Kessler, H. (2010). Cilengitide: the first anti-angiogenic small molecule drug candidate design, synthesis and clinical evaluation. Anti-cancer agents in medicinal chemistry 10, 753-768.
41. Nejjari, M., Hafdi, Z., Dumortier, J., Bringuier, A.F., Feldmann, G., and Scoazec, J.Y. (1999). alpha6beta1 integrin expression in hepatocarcinoma cells: regulation and role in cell adhesion and migration. International journal of cancer Journal international du cancer 83, 518-525.
42. Nejjari, M., Hafdi, Z., Gouysse, G., Fiorentino, M., Beatrix, O., Dumortier, J., Pourreyron, C., Barozzi, C., D'Errico, A., Grigioni, W.F., et al. (2002). Expression, regulation, and function of alpha V integrins in hepatocellular carcinoma: an in vivo and in vitro study. Hepatology (Baltimore, Md) 36, 418-426.
43. Niu, D., Feng, H., and Chen, W.N. (2010). Proteomic analysis of HBV-associated HCC: insights on mechanisms of disease onset and biomarker discovery. Journal of proteomics 73, 1283-1290.
44. Ou, D.P., Tao, Y.M., Tang, F.Q., and Yang, L.Y. (2007). The hepatitis B virus X protein promotes hepatocellular carcinoma metastasis by upregulation of matrix metalloproteinases. International journal of cancer Journal international du cancer 120, 1208-1214.
45. Ozaki, I., Hamajima, H., Matsuhashi, S., and Mizuta, T. (2011). Regulation of TGF-β1-induced proapoptotic signaling by growth factor receptors and extracellular matrix receptor integrins in the liver. Frontiers in Physiology 2.
46. Patsenker, E., Popov, Y., Stickel, F., Schneider, V., Ledermann, M., Sagesser, H., Niedobitek, G., Goodman, S.L., and Schuppan, D. (2009). Pharmacological inhibition of integrin alphavbeta3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis. Hepatology (Baltimore, Md) 50, 1501-1511.
47. Patsenker, E., Popov, Y., Wiesner, M., Goodman, S.L., and Schuppan, D. (2007). Pharmacological inhibition of the vitronectin receptor abrogates PDGF-BB-induced hepatic stellate cell migration and activation in vitro. Journal of hepatology 46, 878-887.
48. Peck-Radosavljevic, M. (2014). Drug therapy for advanced-stage liver cancer. Liver cancer 3, 125-131.
49. Pinzani, M., and Rombouts, K. (2004). Liver fibrosis: from the bench to clinical targets. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 36, 231-242.
50. Puisieux, A., Galvin, K., Troalen, F., Bressac, B., Marcais, C., Galun, E., Ponchel, F., Yakicier, C., Ji, J., and Ozturk, M. (1993). Retinoblastoma and p53 tumor suppressor genes in human hepatoma cell lines. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 7, 1407-1413.
51. Rosenow, F., Ossig, R., Thormeyer, D., Gasmann, P., Schluter, K., Brunner, G., Haier, J., and Eble, J.A. (2008). Integrins as antimetastatic targets of RGD-independent snake venom components in liver metastasis [corrected]. Neoplasia (New York, NY) 10, 168-176.
52. Sarray, S., Luis, J., Ayeb, M.E., and Marrakchi, N. (2013). Snake Venom Peptides: Promising Molecules with Anti-Tumor Effects.
53. Soffietti, R., Trevisan, E., and Ruda, R. (2014). What have we learned from trials on antiangiogenic agents in glioblastoma? Expert review of neurotherapeutics 14, 1-3.
54. Sundaralingam, T., and Gill, S. (2011). Patterns of presentation, referral, and treatment of hepatocellular carcinoma in a pre-sorafenib era: experience of a Canadian provincial cancer agency, Vol 18.
55. Taefi, A., Abrishami, A., Nasseri-Moghaddam, S., Eghtesad, B., and Sherman, M. (2013). Surgical resection versus liver transplant for patients with hepatocellular carcinoma. The Cochrane database of systematic reviews 6, Cd006935.
56. Tan, T.L., Fang, N., Neo, T.L., Singh, P., Zhang, J., Zhou, R., Koh, C.G., Chan, V., Lim, S.G., and Chen, W.N. (2008). Rac1 GTPase is activated by hepatitis B virus replication--involvement of HBX. Biochimica et biophysica acta 1783, 360-374.
57. Tang, R., Kong, F., Hu, L., You, H., Zhang, P., Du, W., and Zheng, K. (2012). Role of hepatitis B virus X protein in regulating LIM and SH3 protein 1 (LASP-1) expression to mediate proliferation and migration of hepatoma cells. Virology journal 9, 163.
58. Tian, B., Li, Y., Ji, X.N., Chen, J., Xue, Q., Ye, S.L., Liu, Y.K., and Tang, Z.Y. (2005). Basement membrane proteins play an active role in the invasive process of human hepatocellular carcinoma cells with high metastasis potential. Journal of cancer research and clinical oncology 131, 80-86.
59. Uhl, P., Fricker, G., Haberkorn, U., and Mier, W. (2014). Current status in the therapy of liver diseases. International journal of molecular sciences 15, 7500-7512.
60. Wilisch-Neumann, A., Kliese, N., Pachow, D., Schneider, T., Warnke, J.P., Braunsdorf, W.E., Bohmer, F.D., Hass, P., Pasemann, D., Helbing, C., et al. (2013). The integrin inhibitor cilengitide affects meningioma cell motility and invasion. Clinical cancer research : an official journal of the American Association for Cancer Research 19, 5402-5412.
61. Wu, Y., Qiao, X., Qiao, S., and Yu, L. (2011). Targeting integrins in hepatocellular carcinoma. In Expert opinion on therapeutic targets, pp. 421-437.
62. Yang, C., Zeisberg, M., Lively, J.C., Nyberg, P., Afdhal, N., and Kalluri, R. (2003). Integrin alpha1beta1 and alpha2beta1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. Cancer research 63, 8312-8317.
63. Yeh, C.H., Peng, H.C., Yang, R.S., and Huang, T.F. (2001). Rhodostomin, a snake venom disintegrin, inhibits angiogenesis elicited by basic fibroblast growth factor and suppresses tumor growth by a selective alpha(v)beta(3) blockade of endothelial cells. Molecular pharmacology 59, 1333-1342.
64. Yen, C.J., Lin, Y.J., Yen, C.S., Tsai, H.W., Tsai, T.F., Chang, K.Y., Huang, W.C., Lin, P.W., Chiang, C.W., and Chang, T.T. (2012). Hepatitis B virus X protein upregulates mTOR signaling through IKKbeta to increase cell proliferation and VEGF production in hepatocellular carcinoma. PloS one 7, e41931.
65. Yu, F.L., Liu, H.J., Lee, J.W., Liao, M.H., and Shih, W.L. (2005). Hepatitis B virus X protein promotes cell migration by inducing matrix metalloproteinase-3. Journal of hepatology 42, 520-527.
66. Zhang, F., Kong, D., Chen, L., Zhang, X., Lian, N., Zhu, X., Lu, Y., and Zheng, S. (2014). Peroxisome proliferator-activated receptor-gamma interrupts angiogenic signal transduction by transrepression of platelet-derived growth factor-beta receptor in hepatic stellate cells. Journal of cell science 127, 305-314.
67. Zhou, X.D. (2002). Recurrence and metastasis of hepatocellular carcinoma: progress and prospects. Hepatobiliary & pancreatic diseases international : HBPD INT 1, 35-41.
68. Zoppi, N., Ritelli, M., Salvi, A., Colombi, M., and Barlati, S. (2007). The FN13 peptide inhibits human tumor cells invasion through the modulation of alpha v beta 3 integrins organization and the inactivation of ILK pathway. Biochimica et biophysica acta 1773, 747-763
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2019-08-28起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2019-08-28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