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系統識別號 U0026-0108201217065400
論文名稱(中文) Epstein-Barr病毒溶裂期蛋白質Rta誘發細胞侵襲和基質金屬蛋白酶九的表現
論文名稱(英文) Induction of Cell Invasion and Matrix Metalloproteinase-9 Expression by the Epstein-Barr Virus Lytic Protein Rta
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 100
學期 2
出版年 101
研究生(中文) 張芳馨
研究生(英文) Fang-Hsin Chang
學號 S46991130
學位類別 碩士
語文別 中文
論文頁數 69頁
口試委員 指導教授-張堯
口試委員-林素芳
口試委員-徐麗君
口試委員-張志鵬
中文關鍵字 EB病毒  鼻咽癌  Rta  基質金屬蛋白酶九  細胞侵襲 
英文關鍵字 EBV  nasopharyngeal carcinoma  Rta  MMP-9  cell invasion 
學科別分類
中文摘要 EB病毒再活化進入溶裂期與鼻咽癌—一種在台灣及中國南部地區盛行的上皮細胞癌症—具有關聯。鼻咽癌具高度侵襲性及轉移性,而其中一個連結EB病毒再活化與此惡性表徵的線索為EB病毒的溶裂期轉活化蛋白質—Zta—會增強上皮細胞移行和侵襲的能力。Rta是另一個EB病毒溶裂期蛋白質,可與Zta共同作用起始EB病毒的再活化,但Rta對於細胞侵襲的影響目前仍為未知。因此在本篇研究中,我們探討Rta是否並且如何促進鼻咽癌細胞的侵襲能力。首先,我們在matrigel侵襲實驗中發現表現Rta會促使細胞侵襲能力增加。經由抗體陣列分析,發現Rta會誘發鼻咽癌細胞產生基質金屬蛋白酶九 (MMP-9),MMP-9為一種在鼻咽癌可經常被偵測到、並且與轉移有關的蛋白酶。透過明膠酶譜法,我們確認Rta誘發MMP-9表現不僅侷限在鼻咽癌細胞,也發生在何杰金氏淋巴癌細胞和口腔鱗狀上皮癌細胞。此外,Rta和Zta對於調控MMP-9並沒有加乘效果。定量RT-PCR和ELISA的結果顯示Rta會增加MMP-9在RNA和蛋白質層次上的表現。透過報導基因分析,我們也發現Rta會活化MMP-9的啟動子。經由蛋白質-DNA陣列分析,我們找到許多可能被Rta所調控的轉錄因子。我們也進一步發現ERK訊息傳遞抑制劑和E2F抑制劑可阻斷Rta所誘發的MMP-9表現,暗示ERK和E2F可能參與Rta調控MMP-9的表現。最重要的是,以siRNA抑制MMP-9的表現可阻斷Rta促進鼻咽癌細胞侵襲能力的現象。總結而論,本篇研究顯示Rta會透過誘發MMP-9的表現促進細胞侵襲,揭露一個Rta參與鼻咽癌進程的可能性。
英文摘要 Epstein-Barr virus (EBV) reactivation into the lytic cycle is associated with nasopharyngeal carcinoma (NPC), an endemic epithelial cancer in Taiwan and southern China. NPC is highly invasive and metastatic, and one clue linking EBV reactivation to this malignant phenotype is that an EBV lytic transactivator Zta can enhance migration and invasion of epithelial cells. Rta is another EBV lytic protein that cooperates with Zta to initiate EBV reactivation, but the effect of Rta on cell invasion remains unknown. In this study, we tested whether and how Rta promotes invasion of NPC cells. First, transient Rta expression enhanced invasiveness of NPC cells in a matrigel invasion assay. Using an antibody array, we found that from NPC cells Rta induced production of matrix metalloproteinase-9 (MMP-9), a metastasis-associated protease generally detected in NPC tumors. Using gelatin zymography, we confirmed Rta-induced MMP9 production not only in NPC cells but also in Hodgkin lymphoma and oral squamous cell carcinoma cells. In addition, there was no synergistic effect on MMP9 when Rta and Zta were co-expressed. Quantitative RT-PCR and ELISA showed Rta-mediated upregulation of MMP-9 at both RNA and protein levels. We also found that Rta can transactivate the MMP-9 promoter by using a reporter assay. Using a protein/DNA array technique we found some candidates of transcription factors regulated by Rta. Furthermore, inhibitors of the ERK signaling and E2F blocked Rta-induced MMP-9 production, suggesting that ERK and E2F may be involved in Rta-regulated MMP-9 expression. Most importantly, inhibition of MMP-9 expression by siRNA blocked Rta-enhanced NPC cell invasion. In conclusion, this study shows that Rta promotes cell invasion through induction of MMP9, revealing a possible role of Rta in NPC progression.
論文目次 中文摘要............................................................................................................................Ⅰ
Abstract...............................................................................................................Ⅱ
致謝....................................................................................................................................Ⅲ
目錄....................................................................................................................................Ⅳ
圖目錄................................................................................................................................Ⅵ
縮寫索引表.......................................................................................................................Ⅶ

緒論
一、Epstein-Barr病毒簡介................................................................................................1
二、EB病毒生活史:潛伏期與溶裂期............................................................................2
三、EB病毒溶裂期蛋白質Rta.........................................................................................4
四、EB病毒相關疾病........................................................................................................6
五、鼻咽癌...........................................................................................................................7
六、EB病毒溶裂期與鼻咽癌之相關性............................................................................8
七、Rta與鼻咽癌的關連性.............................................................................................10
八、基質金屬蛋白酶對癌症的影響.................................................................................11
九、基質金屬蛋白酶九.....................................................................................................12
十、研究動機與假設.........................................................................................................15

材料與方法
一、細胞株及培養方式....................................................................................................16
二、細胞轉染質體DNA或siRNA.................................................................................16
三、質體DNA及siRNA.................................................................................................17
四、質體DNA轉型與製備.............................................................................................17
五、抗體陣列分析............................................................................................................18
六、冷光酶分析................................................................................................................19
七、抽取細胞RNA...........................................................................................................19
八、cDNA之製備............................................................................................................20
九、即時定量PCR...........................................................................................................21
十、西方墨點法................................................................................................................22
十一、酵素免疫分析.........................................................................................................24
十二、明膠酶譜法.............................................................................................................24
十三、細胞侵襲實驗.........................................................................................................25
十四、藥物處理實驗.........................................................................................................25
十五、核質分離實驗.........................................................................................................26
十六、蛋白質/DNA陣列分析..........................................................................................26
十七、抗體........................................................................................................................29
十八、數據分析................................................................................................................29

實驗結果
一、EB病毒溶裂期蛋白質Rta增強鼻咽癌細胞侵襲能力..........................................30
二、Rta誘導鼻咽癌細胞產生基質金屬蛋白酶-9 (MMP-9) .........................................30
三、在MMP-9的調控上Rta和Zta兩者之間並沒有加乘效果..................................31
四、Rta誘發MMP-9 mRNA的表現..............................................................................31
五、Rta活化MMP-9基因的啟動子...............................................................................32
六、Rta會調控許多轉錄因子結合DNA的能力...........................................................32
七、ERK訊息傳遞路徑和E2F在Rta調控MMP-9表現的機制中是必需的............33
八、Rta透過MMP-9增強鼻咽癌細胞的侵襲能力......................................................34
九、結論............................................................................................................................34

討論
一、EB病毒溶裂期蛋白質Rta調控MMP-9的表現....................................................35
二、Rta所誘發的MMP-9幫助鼻咽癌細胞侵襲能力增加...........................................37
三、在MMP-9的調控上,Rta和Zta沒有加乘作用....................................................38
四、Rta誘發MMP-9的潛在免疫調節功能...................................................................39
五、Rta誘發MMP-9表現與之前研究不協調之處.......................................................40
六、MMP-9對於EB病毒之重要性...............................................................................41
七、其他病毒調控MMP-9的表現..................................................................................42
八、抑制MMP-9或其他MMPs的表現在鼻咽癌治療上的潛在應用性.....................42

參考文獻............................................................................................................................44
圖表....................................................................................................................................60
自述......................................................................................................................................69
參考文獻 Adamson, A.L., Darr, D., Holley-Guthrie, E., Johnson, R.A., Mauser, A., Swenson, J., and Kenney, S. (2000). Epstein-Barr virus immediate-early proteins BZLF1 and BRLF1 activate the ATF2 transcription factor by increasing the levels of phosphorylated p38 and c-Jun N-terminal kinases. J Virol 74, 1224-1233.

Ahmad, A., and Stefani, S. (1986). Distant metastases of nasopharyngeal carcinoma: a study of 256 male patients. J Surg Oncol 33, 194-197.

Akool el, S., Kleinert, H., Hamada, F.M., Abdelwahab, M.H., Forstermann, U., Pfeilschifter, J., and Eberhardt, W. (2003). Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuR. Mol Cell Biol 23, 4901-4916.

Al-Sarraf, M., LeBlanc, M., Giri, P.G., Fu, K.K., Cooper, J., Vuong, T., Forastiere, A.A., Adams, G., Sakr, W.A., Schuller, D.E., et al. (1998). Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol 16, 1310-1317.

Alves, F., Vogel, W., Mossie, K., Millauer, B., Hofler, H., and Ullrich, A. (1995). Distinct structural characteristics of discoidin I subfamily receptor tyrosine kinases and complementary expression in human cancer. Oncogene 10, 609-618.

Amalinei, C., Caruntu, I.D., and Balan, R.A. (2007). Biology of metalloproteinases. Rom J Morphol Embryol 48, 323-334.

An, X., Wang, F.H., Ding, P.R., Deng, L., Jiang, W.Q., Zhang, L., Shao, J.Y., and Li, Y.H. (2011). Plasma Epstein-Barr virus DNA level strongly predicts survival in metastatic/recurrent nasopharyngeal carcinoma treated with palliative chemotherapy. Cancer 117, 3750-3757.

Bauer, G. (1983). Quantitative analysis of the cooperative effect between inducers of Epstein-Barr virus antigen synthesis. J Gen Virol 64 (Pt 6), 1337-1346.

Bergers, G., Brekken, R., McMahon, G., Vu, T.H., Itoh, T., Tamaki, K., Tanzawa, K., Thorpe, P., Itohara, S., Werb, Z., et al. (2000). Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2, 737-744.

Bonfil, R.D., Sabbota, A., Nabha, S., Bernardo, M.M., Dong, Z., Meng, H., Yamamoto, H., Chinni, S.R., Lim, I.T., Chang, M., et al. (2006). Inhibition of human prostate cancer growth, osteolysis and angiogenesis in a bone metastasis model by a novel mechanism-based selective gelatinase inhibitor. Int J Cancer 118, 2721-2726.

Bourboulia, D., and Stetler-Stevenson, W.G. (2010). Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin Cancer Biol 20, 161-168.

Brew, K., and Nagase, H. (2010). The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 1803, 55-71.

Burgermeister, E., Chuderland, D., Hanoch, T., Meyer, M., Liscovitch, M., and Seger, R. (2007). Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor gamma. Mol Cell Biol 27, 803-817.

Cabras, G., Decaussin, G., Zeng, Y., Djennaoui, D., Melouli, H., Broully, P., Bouguermouh, A.M., and Ooka, T. (2005). Epstein-Barr virus encoded BALF1 gene is transcribed in Burkitt's lymphoma cell lines and in nasopharyngeal carcinoma's biopsies. J Clin Virol 34, 26-34.

Cai, Y.L., Zheng, Y.M., Cheng, J.R., Wang, W., Zhang, Y.N., Wang, W.H., Wu, Y.S., Zhong, W.M., Li, J., and Mo, Y.K. (2010). [Relationship between clinical stages of nasopharyngeal carcinoma and Epstein-Barr virus antibodies Rta/IgG, EBNA1/IgA, VCA/IgA and EA/IgA]. Nan Fang Yi Ke Da Xue Xue Bao 30, 509-511.

Chang, L.K., Chuang, J.Y., Nakao, M., and Liu, S.T. (2010). MCAF1 and synergistic activation of the transcription of Epstein-Barr virus lytic genes by Rta and Zta. Nucleic Acids Res 38, 4687-4700.

Chang, L.K., Chung, J.Y., Hong, Y.R., Ichimura, T., Nakao, M., and Liu, S.T. (2005). Activation of Sp1-mediated transcription by Rta of Epstein-Barr virus via an interaction with MCAF1. Nucleic Acids Res 33, 6528-6539.

Chang, L.K., Lee, Y.H., Cheng, T.S., Hong, Y.R., Lu, P.J., Wang, J.J., Wang, W.H., Kuo, C.W., Li, S.S., and Liu, S.T. (2004a). Post-translational modification of Rta of Epstein-Barr virus by SUMO-1. J Biol Chem 279, 38803-38812.

Chang, P.J., Chang, Y.S., and Liu, S.T. (1998). Role of Rta in the translation of bicistronic BZLF1 of Epstein-Barr virus. J Virol 72, 5128-5136.

Chang, Y., Lee, H.H., Chang, S.S., Hsu, T.Y., Wang, P.W., Chang, Y.S., Takada, K., and Tsai, C.H. (2004b). Induction of Epstein-Barr virus latent membrane protein 1 by a lytic transactivator Rta. J Virol 78, 13028-13036.

Chang, Y., Lee, H.H., Chen, Y.T., Lu, J., Wu, S.Y., Chen, C.W., Takada, K., and Tsai, C.H. (2006). Induction of the early growth response 1 gene by Epstein-Barr virus lytic transactivator Zta. J Virol 80, 7748-7755.

Chen, L.W., Chang, P.J., Delecluse, H.J., and Miller, G. (2005). Marked variation in response of consensus binding elements for the Rta protein of Epstein-Barr virus. J Virol 79, 9635-9650.

Chen, Y.L., Chen, Y.J., Tsai, W.H., Ko, Y.C., Chen, J.Y., and Lin, S.F. (2009). The Epstein-Barr virus replication and transcription activator, Rta/BRLF1, induces cellular senescence in epithelial cells. Cell Cycle 8, 58-65.

Chien, Y.C., Chen, J.Y., Liu, M.Y., Yang, H.I., Hsu, M.M., Chen, C.J., and Yang, C.S. (2001). Serologic markers of Epstein-Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N Engl J Med 345, 1877-1882.

Chua, H.H., Lee, H.H., Chang, S.S., Lu, C.C., Yeh, T.H., Hsu, T.Y., Cheng, T.H., Cheng, J.T., Chen, M.R., and Tsai, C.H. (2007). Role of the TSG101 gene in Epstein-Barr virus late gene transcription. J Virol 81, 2459-2471.

Chua, H.H., Yeh, T.H., Wang, Y.P., Huang, Y.T., Sheen, T.S., Lo, Y.C., Chou, Y.C., and Tsai, C.H. (2008). Upregulation of discoidin domain receptor 2 in nasopharyngeal carcinoma. Head Neck 30, 427-436.

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 J 18, 1123-1125.
Cochet, C., Martel-Renoir, D., Grunewald, V., Bosq, J., Cochet, G., Schwaab, G., Bernaudin, J.F., and Joab, I. (1993). Expression of the Epstein-Barr virus immediate early gene, BZLF1, in nasopharyngeal carcinoma tumor cells. Virology 197, 358-365.

Coussens, L.M., Tinkle, C.L., Hanahan, D., and Werb, Z. (2000). MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103, 481-490.

Coussens, L.M., and Werb, Z. (1996). Matrix metalloproteinases and the development of cancer. Chem Biol 3, 895-904.

Darr, C.D., Mauser, A., and Kenney, S. (2001). Epstein-Barr virus immediate-early protein BRLF1 induces the lytic form of viral replication through a mechanism involving phosphatidylinositol-3 kinase activation. J Virol 75, 6135-6142.

de-Vathaire, F., Sancho-Garnier, H., de-The, H., Pieddeloup, C., Schwaab, G., Ho, J.H., Ellouz, R., Micheau, C., Cammoun, M., Cachin, Y., et al. (1988). Prognostic value of EBV markers in the clinical management of nasopharyngeal carcinoma (NPC): a multicenter follow-up study. Int J Cancer 42, 176-181.

DeWire, S.M., McVoy, M.A., and Damania, B. (2002). Kinetics of expression of rhesus monkey rhadinovirus (RRV) and identification and characterization of a polycistronic transcript encoding the RRV Orf50/Rta, RRV R8, and R8.1 genes. J Virol 76, 9819-9831.

Du, C.W., Wen, B.G., Li, D.R., Peng, X., Hong, C.Q., Chen, J.Y., Lin, Z.Z., Hong, X., Lin, Y.C., Xie, L.X., et al. (2006). Arsenic trioxide reduces the invasive and metastatic properties of nasopharyngeal carcinoma cells in vitro. Braz J Med Biol Res 39, 677-685.

Du, H.Y., Olivo, M., Mahendran, R., Huang, Q., Shen, H.M., Ong, C.N., and Bay, B.H. (2007). Hypericin photoactivation triggers down-regulation of matrix metalloproteinase-9 expression in well-differentiated human nasopharyngeal cancer cells. Cell Mol Life Sci 64, 979-988.

Edwards, R.H., Marquitz, A.R., and Raab-Traub, N. (2008). Epstein-Barr virus BART microRNAs are produced from a large intron prior to splicing. J Virol 82, 9094-9106.

Egeblad, M., and Werb, Z. (2002). New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2, 161-174.
Epstein, M.A., Achong, B.G., and Barr, Y.M. (1964). Virus Particles in Cultured Lymphoblasts from Burkitt's Lymphoma. Lancet 1, 702-703.

Fang, C.Y., Lee, C.H., Wu, C.C., Chang, Y.T., Yu, S.L., Chou, S.P., Huang, P.T., Chen, C.L., Hou, J.W., Chang, Y., et al. (2009). Recurrent chemical reactivations of EBV promotes genome instability and enhances tumor progression of nasopharyngeal carcinoma cells. Int J Cancer 124, 2016-2025.

Feederle, R., Kost, M., Baumann, M., Janz, A., Drouet, E., Hammerschmidt, W., and Delecluse, H.J. (2000). The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. EMBO J 19, 3080-3089.

Feng, B.J., Jalbout, M., Ayoub, W.B., Khyatti, M., Dahmoul, S., Ayad, M., Maachi, F., Bedadra, W., Abdoun, M., Mesli, S., et al. (2007). Dietary risk factors for nasopharyngeal carcinoma in Maghrebian countries. Int J Cancer 121, 1550-1555.

Feng, P., Chan, S.H., Soo, M.Y., Liu, D., Guan, M., Ren, E.C., and Hu, H. (2001). Antibody response to Epstein-Barr virus Rta protein in patients with nasopharyngeal carcinoma: a new serologic parameter for diagnosis. Cancer 92, 1872-1880.

Feng, P., Ren, E.C., Liu, D., Chan, S.H., and Hu, H. (2000). Expression of Epstein-Barr virus lytic gene BRLF1 in nasopharyngeal carcinoma: potential use in diagnosis. J Gen Virol 81, 2417-2423.

Gruffat, H., Duran, N., Buisson, M., Wild, F., Buckland, R., and Sergeant, A. (1992). Characterization of an R-binding site mediating the R-induced activation of the Epstein-Barr virus BMLF1 promoter. J Virol 66, 46-52.

Gruffat, H., Manet, E., Rigolet, A., and Sergeant, A. (1990). The enhancer factor R of Epstein-Barr virus (EBV) is a sequence-specific DNA binding protein. Nucleic Acids Res 18, 6835-6843.

Gruffat, H., and Sergeant, A. (1994). Characterization of the DNA-binding site repertoire for the Epstein-Barr virus transcription factor R. Nucleic Acids Res 22, 1172-1178.

Hardwick, J.M., Lieberman, P.M., and Hayward, S.D. (1988). A new Epstein-Barr virus transactivator, R, induces expression of a cytoplasmic early antigen. J Virol 62, 2274-2284.
Hayashida, T., Decaestecker, M., and Schnaper, H.W. (2003). Cross-talk between ERK MAP kinase and Smad signaling pathways enhances TGF-beta-dependent responses in human mesangial cells. FASEB J 17, 1576-1578.

Henle, G., and Henle, W. (1976). Epstein-Barr virus-specific IgA serum antibodies as an outstanding feature of nasopharyngeal carcinoma. Int J Cancer 17, 1-7.

Henle, G., Henle, W., and Diehl, V. (1968). Relation of Burkitt's tumor-associated herpes-ytpe virus to infectious mononucleosis. Proc Natl Acad Sci U S A 59, 94-101.
Henle, W., Ho, J.H., Henle, G., Chau, J.C., and Kwan, H.C. (1977). Nasopharyngeal carcinoma: significance of changes in Epstein-Barr virus-related antibody patterns following therapy. Int J Cancer 20, 663-672.

Ho, C.H., Chen, C.L., Li, W.Y., and Chen, C.J. (2009). Decoy receptor 3, upregulated by Epstein-Barr virus latent membrane protein 1, enhances nasopharyngeal carcinoma cell migration and invasion. Carcinogenesis 30, 1443-1451.

Ho, C.H., Hsu, C.F., Fong, P.F., Tai, S.K., Hsieh, S.L., and Chen, C.J. (2007). Epstein-Barr virus transcription activator Rta upregulates decoy receptor 3 expression by binding to its promoter. J Virol 81, 4837-4847.

Horikawa, T., Yoshizaki, T., Sheen, T.S., Lee, S.Y., and Furukawa, M. (2000). Association of latent membrane protein 1 and matrix metalloproteinase 9 with metastasis in nasopharyngeal carcinoma. Cancer 89, 715-723.

Hsu, M.M., and Tu, S.M. (1983). Nasopharyngeal carcinoma in Taiwan. Clinical manifestations and results of therapy. Cancer 52, 362-368.

Hua, J., and Muschel, R.J. (1996). Inhibition of matrix metalloproteinase 9 expression by a ribozyme blocks metastasis in a rat sarcoma model system. Cancer Res 56, 5279-5284.

Huang, S.Y., Hsieh, M.J., Chen, C.Y., Chen, Y.J., Chen, J.Y., Chen, M.R., Tsai, C.H., Lin, S.F., and Hsu, T.Y. (2012). Epstein-Barr virus Rta-mediated transactivation of p21 and 14-3-3sigma arrests cells at the G1/S transition by reducing cyclin E/CDK2 activity. J Gen Virol 93, 139-149.

Itoh, T., Tanioka, M., Matsuda, H., Nishimoto, H., Yoshioka, T., Suzuki, R., and Uehira, M. (1999). Experimental metastasis is suppressed in MMP-9-deficient mice. Clin Exp Metastasis 17, 177-181.

Jiang, Y., and Muschel, R.J. (2002). Regulation of matrix metalloproteinase-9 (MMP-9) by translational efficiency in murine prostate carcinoma cells. Cancer Res 62, 1910-1914.

John, A., and Tuszynski, G. (2001). The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res 7, 14-23.

Johnson, G.L., and Lapadat, R. (2002). Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298, 1911-1912.

Johnson, J.L., Pillai, S., Pernazza, D., Sebti, S.M., Lawrence, N.J., and Chellappan, S.P. (2012). Regulation of matrix metalloproteinase genes by E2F transcription factors: Rb-Raf-1 interaction as a novel target for metastatic disease. Cancer Res 72, 516-526.

Kaidar-Person, O., Kuten, J., Atrash, F., Billan, S., and Kuten, A. (2012). Brain metastasis of nasopharyngeal carcinoma: a case report and literature review. Case Report Med 2012, 405917.

Kessenbrock, K., Plaks, V., and Werb, Z. (2010). Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52-67.

Kube, D., Vockerodt, M., Weber, O., Hell, K., Wolf, J., Haier, B., Grasser, F.A., Muller-Lantzsch, N., Kieff, E., Diehl, V., et al. (1999). Expression of epstein-barr virus nuclear antigen 1 is associated with enhanced expression of CD25 in the Hodgkin cell line L428. J Virol 73, 1630-1636.

Kuilman, T., and Peeper, D.S. (2009). Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9, 81-94.

Kupferman, M.E., Fini, M.E., Muller, W.J., Weber, R., Cheng, Y., and Muschel, R.J. (2000). Matrix metalloproteinase 9 promoter activity is induced coincident with invasion during tumor progression. Am J Pathol 157, 1777-1783.

Kutok, J.L., and Wang, F. (2006). Spectrum of Epstein-Barr virus-associated diseases. Annu Rev Pathol 1, 375-404.
Lan, Y.Y., Hsiao, J.R., Chang, K.C., Chang, J.S., Chen, C.W., Lai, H.C., Wu, S.Y., Yeh, T.H., Chang, F.H., Lin, W.H., et al. (2012). Epstein-Barr Virus Latent Membrane Protein 2A Promotes Invasion of Nasopharyngeal Carcinoma Cells through ERK/Fra-1-Mediated Induction of Matrix Metalloproteinase 9. J Virol 86, 6656-6667.

Lee, S., Zheng, M., Kim, B., and Rouse, B.T. (2002). Role of matrix metalloproteinase-9 in angiogenesis caused by ocular infection with herpes simplex virus. J Clin Invest 110, 1105-1111.

Lee, Y.H., Chiu, Y.F., Wang, W.H., Chang, L.K., and Liu, S.T. (2008). Activation of the ERK signal transduction pathway by Epstein-Barr virus immediate-early protein Rta. J Gen Virol 89, 2437-2446.

Li, Y., Webster-Cyriaque, J., Tomlinson, C.C., Yohe, M., and Kenney, S. (2004). Fatty acid synthase expression is induced by the Epstein-Barr virus immediate-early protein BRLF1 and is required for lytic viral gene expression. J Virol 78, 4197-4206.

Lin, J.C., Wang, W.Y., Chen, K.Y., Wei, Y.H., Liang, W.M., Jan, J.S., and Jiang, R.S. (2004). Quantification of plasma Epstein-Barr virus DNA in patients with advanced nasopharyngeal carcinoma. N Engl J Med 350, 2461-2470.

Lin, M.L., Lu, Y.C., Chung, J.G., Wang, S.G., Lin, H.T., Kang, S.E., Tang, C.H., Ko, J.L., and Chen, S.S. (2010). Down-regulation of MMP-2 through the p38 MAPK-NF-kappaB-dependent pathway by aloe-emodin leads to inhibition of nasopharyngeal carcinoma cell invasion. Mol Carcinog 49, 783-797.

Liotta, L.A. (1986). Tumor invasion and metastases--role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res 46, 1-7.

Liotta, L.A., Tryggvason, K., Garbisa, S., Hart, I., Foltz, C.M., and Shafie, S. (1980). Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 284, 67-68.

Liu, C., Sista, N.D., and Pagano, J.S. (1996). Activation of the Epstein-Barr virus DNA polymerase promoter by the BRLF1 immediate-early protein is mediated through USF and E2F. J Virol 70, 2545-2555.

Liu, M.Y., Chang, Y.L., Ma, J., Yang, H.L., Hsu, M.M., Chen, C.J., Chen, J.Y., and Yang, C.S. (1997). Evaluation of multiple antibodies to Epstein-Barr virus as markers for detecting patients with nasopharyngeal carcinoma. J Med Virol 52, 262-269.

Liu, W., and Han, H.X. (2006). [Expression of CD25+ lymphocytes in nasopharyngeal carcinoma and its association with EBV infection]. Nan Fang Yi Ke Da Xue Xue Bao 26, 94-97.

Liu, Y., Tong, Z., Li, T., Chen, Q., Zhuo, L., Li, W., Wu, R.C., and Yu, C. (2012). Hepatitis B virus X protein stabilizes AIB1 protein and cooperates with it to promote human hepatocellular carcinoma cell invasiveness. Hepatology.

Liu, Z., Li, L., Yang, Z., Luo, W., Li, X., Yang, H., Yao, K., Wu, B., and Fang, W. (2010). Increased expression of MMP9 is correlated with poor prognosis of nasopharyngeal carcinoma. BMC Cancer 10, 270.

Lo, Y.M., Chan, L.Y., Chan, A.T., Leung, S.F., Lo, K.W., Zhang, J., Lee, J.C., Hjelm, N.M., Johnson, P.J., and Huang, D.P. (1999a). Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res 59, 5452-5455.

Lo, Y.M., Chan, L.Y., Lo, K.W., Leung, S.F., Zhang, J., Chan, A.T., Lee, J.C., Hjelm, N.M., Johnson, P.J., and Huang, D.P. (1999b). Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 59, 1188-1191.

Lochter, A., Sternlicht, M.D., Werb, Z., and Bissell, M.J. (1998). The significance of matrix metalloproteinases during early stages of tumor progression. Ann N Y Acad Sci 857, 180-193.

Lu, J., Chua, H.H., Chen, S.Y., Chen, J.Y., and Tsai, C.H. (2003). Regulation of matrix metalloproteinase-1 by Epstein-Barr virus proteins. Cancer Res 63, 256-262.

Lukac, D.M., Renne, R., Kirshner, J.R., and Ganem, D. (1998). Reactivation of Kaposi's sarcoma-associated herpesvirus infection from latency by expression of the ORF 50 transactivator, a homolog of the EBV R protein. Virology 252, 304-312.

Lynch, C.C., and Matrisian, L.M. (2002). Matrix metalloproteinases in tumor-host cell communication. Differentiation 70, 561-573.

Lynn, T., Tu, S., Hirayama, T., and Kawamura, A., Jr. (1973). Nasopharyngeal carcinoma and Epstein-Barr virus. I. Factors related to the anti-VCA antibody. Jpn J Exp Med 43, 121-133.

Manet, E., Allera, C., Gruffat, H., Mikaelian, I., Rigolet, A., and Sergeant, A. (1993). The acidic activation domain of the Epstein-Barr virus transcription factor R interacts in vitro with both TBP and TFIIB and is cell-specifically potentiated by a proline-rich region. Gene Expr 3, 49-59.

Manet, E., Rigolet, A., Gruffat, H., Giot, J.F., and Sergeant, A. (1991). Domains of the Epstein-Barr virus (EBV) transcription factor R required for dimerization, DNA binding and activation. Nucleic Acids Res 19, 2661-2667.

Mannick, J.B., Asano, K., Izumi, K., Kieff, E., and Stamler, J.S. (1994). Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation. Cell 79, 1137-1146.

Marks, J.E., Phillips, J.L., and Menck, H.R. (1998). The National Cancer Data Base report on the relationship of race and national origin to the histology of nasopharyngeal carcinoma. Cancer 83, 582-588.

Martel-Renoir, D., Grunewald, V., Touitou, R., Schwaab, G., and Joab, I. (1995). Qualitative analysis of the expression of Epstein-Barr virus lytic genes in nasopharyngeal carcinoma biopsies. J Gen Virol 76 ( Pt 6), 1401-1408.

Matsuo, T., Heller, M., Petti, L., O'Shiro, E., and Kieff, E. (1984). Persistence of the entire Epstein-Barr virus genome integrated into human lymphocyte DNA. Science 226, 1322-1325.

Meissner, M., Berlinski, B., Doll, M., Hrgovic, I., Laubach, V., Reichenbach, G., Kippenberger, S., Gille, J., and Kaufmann, R. (2011). AP1-dependent repression of TGFalpha-mediated MMP9 upregulation by PPARdelta agonists in keratinocytes. Exp Dermatol 20, 425-429.

Micheau, C., Rilke, F., and Pilotti, S. (1978). Proposal for a new histopathological classification of the carcinomas of the nasopharynx. Tumori 64, 513-518.

Miller, G. (1990). The switch between latency and replication of Epstein-Barr virus. J Infect Dis 161, 833-844.

Morris, M.A., Dawson, C.W., and Young, L.S. (2009). Role of the Epstein-Barr virus-encoded latent membrane protein-1, LMP1, in the pathogenesis of nasopharyngeal carcinoma. Future Oncol 5, 811-825.

Nakahara, H., Howard, L., Thompson, E.W., Sato, H., Seiki, M., Yeh, Y., and Chen, W.T. (1997). Transmembrane/cytoplasmic domain-mediated membrane type 1-matrix metalloprotease docking to invadopodia is required for cell invasion. Proc Natl Acad Sci U S A 94, 7959-7964.

Nakajima, M., Welch, D.R., Belloni, P.N., and Nicolson, G.L. (1987). Degradation of basement membrane type IV collagen and lung subendothelial matrix by rat mammary adenocarcinoma cell clones of differing metastatic potentials. Cancer Res 47, 4869-4876.

Nakajima, M., Welch, D.R., Wynn, D.M., Tsuruo, T., and Nicolson, G.L. (1993). Serum and plasma M(r) 92,000 progelatinase levels correlate with spontaneous metastasis of rat 13762NF mammary adenocarcinoma. Cancer Res 53, 5802-5807.

Nikkola, J., Vihinen, P., Vuoristo, M.S., Kellokumpu-Lehtinen, P., Kahari, V.M., and Pyrhonen, S. (2005). High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. Clin Cancer Res 11, 5158-5166.

Olaso, E., Labrador, J.P., Wang, L., Ikeda, K., Eng, F.J., Klein, R., Lovett, D.H., Lin, H.C., and Friedman, S.L. (2002). Discoidin domain receptor 2 regulates fibroblast proliferation and migration through the extracellular matrix in association with transcriptional activation of matrix metalloproteinase-2. J Biol Chem 277, 3606-3613.

Parkin, D.M., Bray, F., Ferlay, J., and Pisani, P. (2005). Global cancer statistics, 2002. CA Cancer J Clin 55, 74-108.

Pathmanathan, R., Prasad, U., Sadler, R., Flynn, K., and Raab-Traub, N. (1995). Clonal proliferations of cells infected with Epstein-Barr virus in preinvasive lesions related to nasopharyngeal carcinoma. N Engl J Med 333, 693-698.

Perez, C.A., Devineni, V.R., Marcial-Vega, V., Marks, J.E., Simpson, J.R., and Kucik, N. (1992). Carcinoma of the nasopharynx: factors affecting prognosis. Int J Radiat Oncol Biol Phys 23, 271-280.

Pitti, R.M., Marsters, S.A., Lawrence, D.A., Roy, M., Kischkel, F.C., Dowd, P., Huang, A., Donahue, C.J., Sherwood, S.W., Baldwin, D.T., et al. (1998). Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature 396, 699-703.

Puyraimond, A., Weitzman, J.B., Babiole, E., and Menashi, S. (1999). Examining the relationship between the gelatinolytic balance and the invasive capacity of endothelial cells. J Cell Sci 112 ( Pt 9), 1283-1290.

Quinlivan, E.B., Holley-Guthrie, E.A., Norris, M., Gutsch, D., Bachenheimer, S.L., and Kenney, S.C. (1993). Direct BRLF1 binding is required for cooperative BZLF1/BRLF1 activation of the Epstein-Barr virus early promoter, BMRF1. Nucleic Acids Res 21, 1999-2007.

Raab-Traub, N., and Flynn, K. (1986). The structure of the termini of the Epstein-Barr virus as a marker of clonal cellular proliferation. Cell 47, 883-889.

Ragoczy, T., Heston, L., and Miller, G. (1998). The Epstein-Barr virus Rta protein activates lytic cycle genes and can disrupt latency in B lymphocytes. J Virol 72, 7978-7984.

Ragoczy, T., and Miller, G. (2001). Autostimulation of the Epstein-Barr virus BRLF1 promoter is mediated through consensus Sp1 and Sp3 binding sites. J Virol 75, 5240-5251.

Ram, M., Sherer, Y., and Shoenfeld, Y. (2006). Matrix metalloproteinase-9 and autoimmune diseases. J Clin Immunol 26, 299-307.

Razak, A.R., Siu, L.L., Liu, F.F., Ito, E., O'Sullivan, B., and Chan, K. (2010). Nasopharyngeal carcinoma: the next challenges. Eur J Cancer 46, 1967-1978.

Reddy, S.P., Raslan, W.F., Gooneratne, S., Kathuria, S., and Marks, J.E. (1995). Prognostic significance of keratinization in nasopharyngeal carcinoma. Am J Otolaryngol 16, 103-108.

Redondo-Munoz, J., Ugarte-Berzal, E., Terol, M.J., Van den Steen, P.E., Hernandez del Cerro, M., Roderfeld, M., Roeb, E., Opdenakker, G., Garcia-Marco, J.A., and Garcia-Pardo, A. (2010). Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain. Cancer Cell 17, 160-172.

Sabin, R.J., and Anderson, R.M. (2011). Cellular Senescence - its role in cancer and the response to ionizing radiation. Genome Integr 2, 7.

Sehgal, G., Hua, J., Bernhard, E.J., Sehgal, I., Thompson, T.C., and Muschel, R.J. (1998). Requirement for matrix metalloproteinase-9 (gelatinase B) expression in metastasis by murine prostate carcinoma. Am J Pathol 152, 591-596.

Shanmugaratnam, K. (1978). Histological typing of nasopharyngeal carcinoma. IARC Sci Publ, 3-12.

Sheu, B.C., Hsu, S.M., Ho, H.N., Lien, H.C., Huang, S.C., and Lin, R.H. (2001). A novel role of metalloproteinase in cancer-mediated immunosuppression. Cancer Res 61, 237-242.

Shi, M., Liu, D., Duan, H., Han, C., Wei, B., Qian, L., Chen, C., Guo, L., Hu, M., Yu, M., et al. (2010). Catecholamine up-regulates MMP-7 expression by activating AP-1 and STAT3 in gastric cancer. Mol Cancer 9, 269.

Shin, S.Y., Kim, J.H., Baker, A., Lim, Y., and Lee, Y.H. (2010). Transcription factor Egr-1 is essential for maximal matrix metalloproteinase-9 transcription by tumor necrosis factor alpha. Mol Cancer Res 8, 507-519.

Sixbey, J.W., Nedrud, J.G., Raab-Traub, N., Hanes, R.A., and Pagano, J.S. (1984). Epstein-Barr virus replication in oropharyngeal epithelial cells. N Engl J Med 310, 1225-1230.

Sixbey, J.W., Vesterinen, E.H., Nedrud, J.G., Raab-Traub, N., Walton, L.A., and Pagano, J.S. (1983). Replication of Epstein-Barr virus in human epithelial cells infected in vitro. Nature 306, 480-483.

Sternlicht, M.D., and Werb, Z. (2001). How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17, 463-516.

Sun, R., Lin, S.F., Gradoville, L., Yuan, Y., Zhu, F., and Miller, G. (1998). A viral gene that activates lytic cycle expression of Kaposi's sarcoma-associated herpesvirus. Proc Natl Acad Sci U S A 95, 10866-10871.

Swenson, J.J., Holley-Guthrie, E., and Kenney, S.C. (2001). Epstein-Barr virus immediate-early protein BRLF1 interacts with CBP, promoting enhanced BRLF1 transactivation. J Virol 75, 6228-6234.

Takeshita, H., Yoshizaki, T., Miller, W.E., Sato, H., Furukawa, M., Pagano, J.S., and Raab-Traub, N. (1999). Matrix metalloproteinase 9 expression is induced by Epstein-Barr virus latent membrane protein 1 C-terminal activation regions 1 and 2. J Virol 73, 5548-5555.

Tchougounova, E., Lundequist, A., Fajardo, I., Winberg, J.O., Abrink, M., and Pejler, G. (2005). A key role for mast cell chymase in the activation of pro-matrix metalloprotease-9 and pro-matrix metalloprotease-2. J Biol Chem 280, 9291-9296.

Vockerodt, M., Tesch, H., and Kube, D. (2001). Epstein-Barr virus latent membrane protein-1 activates CD25 expression in lymphoma cells involving the NFkappaB pathway. Genes Immun 2, 433-441.

Vokes, E.E., Liebowitz, D.N., and Weichselbaum, R.R. (1997). Nasopharyngeal carcinoma. Lancet 350, 1087-1091.

Vu, T.H., Shipley, J.M., Bergers, G., Berger, J.E., Helms, J.A., Hanahan, D., Shapiro, S.D., Senior, R.M., and Werb, Z. (1998). MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411-422.

Wang, L., Wakisaka, N., Tomlinson, C.C., DeWire, S.M., Krall, S., Pagano, J.S., and Damania, B. (2004). The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV-8) K1 protein induces expression of angiogenic and invasion factors. Cancer Res 64, 2774-2781.

Ward, M.H., Pan, W.H., Cheng, Y.J., Li, F.H., Brinton, L.A., Chen, C.J., Hsu, M.M., Chen, I.H., Levine, P.H., Yang, C.S., et al. (2000). Dietary exposure to nitrite and nitrosamines and risk of nasopharyngeal carcinoma in Taiwan. Int J Cancer 86, 603-609.
Wee, J., Tan, E.H., Tai, B.C., Wong, H.B., Leong, S.S., Tan, T., Chua, E.T., Yang, E., Lee, K.M., Fong, K.W., et al. (2005). Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol 23, 6730-6738.

Whitehouse, A., Carr, I.M., Griffiths, J.C., and Meredith, D.M. (1997). The herpesvirus saimiri ORF50 gene, encoding a transcriptional activator homologous to the Epstein-Barr virus R protein, is transcribed from two distinct promoters of different temporal phases. J Virol 71, 2550-2554.

Wiercinska, E., Naber, H.P., Pardali, E., van der Pluijm, G., van Dam, H., and ten Dijke, P. (2011). The TGF-beta/Smad pathway induces breast cancer cell invasion through the up-regulation of matrix metalloproteinase 2 and 9 in a spheroid invasion model system. Breast Cancer Res Treat 128, 657-666.

Winum, J.Y., Scozzafava, A., Montero, J.L., and Supuran, C.T. (2006). Therapeutic potential of sulfamides as enzyme inhibitors. Med Res Rev 26, 767-792.

Xu, L., Peng, H., Wu, D., Hu, K., Goldring, M.B., Olsen, B.R., and Li, Y. (2005). Activation of the discoidin domain receptor 2 induces expression of matrix metalloproteinase 13 associated with osteoarthritis in mice. J Biol Chem 280, 548-555.

Yoshizaki, T., Miwa, H., Takeshita, H., Sato, H., and Furukawa, M. (2000). Elevation of antibody against Epstein-Barr virus genes BRLF1 and BZLF1 in nasopharyngeal carcinoma. J Cancer Res Clin Oncol 126, 69-73.

Yoshizaki, T., Sato, H., Murono, S., Pagano, J.S., and Furukawa, M. (1999). Matrix metalloproteinase 9 is induced by the Epstein-Barr virus BZLF1 transactivator. Clin Exp Metastasis 17, 431-436.

Young, L.S., and Rickinson, A.B. (2004). Epstein-Barr virus: 40 years on. Nat Rev Cancer 4, 757-768.

Yu, Q., and Stamenkovic, I. (1999). Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes Dev 13, 35-48.

Zhang, J.X., Chen, H.L., Zong, Y.S., Chan, K.H., Nicholls, J., Middeldorp, J.M., Sham, J.S., Griffin, B.E., and Ng, M.H. (1998). Epstein-Barr virus expression within keratinizing nasopharyngeal carcinoma. J Med Virol 55, 227-233.

Zhao, X., and Benveniste, E.N. (2008). Transcriptional activation of human matrix metalloproteinase-9 gene expression by multiple co-activators. J Mol Biol 383, 945-956.

zur Hausen, H., Schulte-Holthausen, H., Klein, G., Henle, W., Henle, G., Clifford, P., and Santesson, L. (1970). EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx. Nature 228, 1056-1058.
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