臺灣博碩士論文加值系統

癌細胞的轉移擴散往往是癌症患者在臨床治療上預後的重要指標，也是主要導致癌症病人死亡的原因。有許多文獻指出在癌症的化學預防上胰蛋白酶抑制劑(trypsin inhibitor)已有許多顯著的生物活性，但是對於其是否會抑制癌症的轉移與其中的詳細機轉至今仍不清楚。在本篇論文中，我們首次證實由相思仔所萃取的胰蛋白酶抑制劑(Acacia confuse trypsin inhibitor ; ACTI)可有效抑制多種肺癌細胞(A549, H1299, and Lewis lung carcinoma (LLC))的細胞侵襲(invasion)、移動(motility)、細胞-基質間的貼附(cell-matrix adhesion)與細胞分泌基質金屬蛋白酶-2、-9 (matrix metalloproteinase (MMP)-2, -9)、尿激酶型纖溶酶原激活物(urokinase-type plasminogen activator; u-PA)的能力。利用西方墨點法，探討其中可能參與的訊息傳遞路徑，證實在A549細胞中ACTI可顯著抑制p-ERK1/2、p-Src、c-Fos與NF-kB的表達，但是對於p-p38與p-Akt則是沒有顯著的影響。此外ACTI也可顯著抑制由12-O-tetradecano-ylphorbol-13-acetate (TPA)所誘導A549細胞細胞的移動能力、MMP-9分泌與p-ERK1/2的表達。最後在動物實驗中，我們利用C57BL/6 老鼠在皮下種植預先處理ACTI的Lewis lung carcinoma，與控制組作比較，會明顯抑制腫瘤的大小。

The invasive ability of tumor cells is a key factor for metastasis and a major cause for treatment failure. Although trypsin inhibitor have been widely recognized to possess several potential as cancer chemopreventive agents, however, limited studies have been available concerning the inhibitory effects of these protein for tumor metastasis. Here, we demonstrated that Acacia confuse trypsin inhibitor (ACTI) could significantly inhibit the invasion, motility, cell-matrix adhesion, secretion of matrix metalloproteinase (MMP)-2, -9, or urokinase-type plasminogen activator (u-PA) of lung cancer cells (A549, H1299, and Lewis lung carcinoma (LLC)). To investigate the possible mechanisms involved in these events, we performed Western blot analysis to find that ACTI inhibited phosphorylation of ERK1/2 and Src, but had no effects on the phosphorylation of p38 and Akt. A treatment with ACTI to A549 cells also inhibited the expression of NF-kB and c-Fos in nuclear extract as shown by Western blot. ACTI inhibited the phosphorylation of ERK1/2, the activity of MMP-9 and cell invasiveness after 12-O-tetradecanoylphorbol-13-acetate (TPA) induction. Finally, these compounds were evidenced by its inhibition on the tumor growth of LLC cells in vivo. Taken together, these findings suggested that ACTI could reduce the invasion and metastasis of lung cancer cells in vivo and in vitro, thereby constituting an adjuvant treatment for metastasis.

目錄
目錄………………………………………………………………1
中英文摘要…………………………………………………………2
縮寫檢索表…………………………………………………………4
壹、緒論……………………………………………………………7
貳、研究動機………………………………………………………26
叁、實驗材料及方法………………………………………………27
肆、實驗結果………………………………………………………41
伍、討論……………………………………………………………47
陸、參考文獻………………………………………………………53
柒、圖表與圖表說明………………………………………………76
捌、附圖表…………………………………………………………86

陸、參考文獻
行政院衛生署2005年十大死因統計.
張永勳 (2000年)，臺灣原住民藥用植物彙編，張永勳研究計畫主持，行政院衛生署中醫藥委員會出版P451-455.
Aljada A, Ghanim H, Mohanty P, Hofmeyer D, Tripathy D, Dandona P,（2001）, Hydrocortisone suppresses intranuclear activator- protein -1 (AP-1) binding activity in mononuclear cells and plasma matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9). The Journal of Clinical Endocrinology and Metabolism , 86; 5988-5991.
Alvarez OA, Carmichael DF, DeClerck YA（1990）, Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. Journal of the National Cancer Institute , 82; 589-595.
Arroyo AG, Genís L, Gonzalo P, Matías-Román S, Pollán A, Gálvez BG.（2007）, Matrix metalloproteinases: new routes to the use of MT1-MMP as a therapeutic target in angiogenesis-related disease. Current Pharmaceutical Design, 13; 1787-1802.
Attiga FA, Fernandez PM, Weeraratna AT, Manyak MJ, Patierno SR（2000）, Inhibitors of prostaglandin synthesis inhibit human prostate tumor cell invasiveness and reduce the release of matrix metalloproteinases. Cancer Research ,60; 4629-4637.
Badier-Commander C, Verbeuren T, Lebard C, Michel JB, Jacob MP.（2000）, Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation. Journal of Pathology ,192; 105-112.
Bhattacharyya A, Rai S, Babu CR.（2007）, A trypsin and chymotrypsin inhibitor from Caesalpinia bonduc seeds: isolation, partial characterization and insecticidal properties. Plant Physiology and Biochemistry, 45; 169-77.
Billings PC, St Clair W, Owen AJ, Kennedy AR.（1988）, Potential intracellular target proteins of the anticarcinogenic Bowman Birk protease inhibitor identified by affinity chromatography. Cancer Research, 48;1798-1802.
Boone TC, Johnson MJ, De Clerck YA, Langley KE.（1990）, cDNA cloning and expression of a metalloproteinase inhibitor related to tissue inhibitor of metalloproteinases. Proceedings of the National Academy of Sciences of the United States of America,87; 2800-2804.
Borrirukwanit K, Lafleur MA, Mercuri FA, Blick T, Price JT, Fridman R, Pereira JJ, Leardkamonkarn V, Thompson EW.（2007）,. The type I collagen induction of MT1-MMP-mediated MMP-2 activation is repressed by alphaVbeta3 integrin in human breast cancer cells. Journal of The International Society, 26; 291-305.
Boyd PJ, Doyle J, Gee E, Pallan S, Haas TL.（2005）, MAPK signaling regulates endothelial cell assembly into networks and expression of MT1-MMP and MMP-2. American Journal of Physiology Cell Physiology, 288; C659-C668.
Dy GK, Jett JR, Geoffroy FJ, Krewer KD, Tazelaar H, Maurer M, Rowland K, Mailliard J, Krook J, Dakhil S, Kutteh L, Kugler J, Wender D.（2006）, A systematic review and meta-analysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer. Journal of Thoracic Oncology,1; 611-621.
Chen YW, Huang SC, Lin-Shiau SY, Lin JK.（2006）, trypsin inhibitortrypsin inhibitorabates proteasome function and suppresses the proliferation of MCF7 breast cancer cells through accumulation of MAP kinase phosphatase-1. Carcinogenesis , 26; 1296-1306.
Cheng JC, Chou CH, Kuo ML, Hsieh CY.（2006）, Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene , 25; 7009-7018.
Cho NH, Hong KP, Hong SH, Kang S, Chung KY, Cho SH.（2004）, MMP expression profiling in recurred stage IB lung cancer. Oncogene , 23; 845-851.
Choi YA, Lim HK, Kim JR, Lee CH, Kim YJ, Kang SS, Baek SH.（2004）, Group IB secretory phospholipase A2 promotes matrix metalloproteinase-2-mediated cell migration via the phosphatidylinositol 3-kinase and Akt pathway. The Journal of Biological Chemistry ,279 ; 36579-36585.
Chu SC, Chiou HL, Chen PN, Yang SF, Hsieh YS.（2004）, Silibinin inhibits the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2. Molecular Carcinogenesis , 40; 143-149.
Clark DA, Day R, Seidah N, Moody TW, Cuttitta F, Davis TP.（1993）, Protease inhibitors suppress in vitro growth of human small cell lung cancer. Peptides, 14; 1021-1028.
Clark RA, Stone PJ, El Hag A, Calore JD, Franzblau C.（1981）, Myeloperoxidase-catalyzed inactivation of alpha 1-protease inhibitor by human neutrophils. The Journal of Biological Chemistry ,256; 3348-3353.
Correa, P. (1981), Epidemiological correlations between diet and cancer frequency. Cancer Research, 41; 3685-3690.
De Clerck Y, Szpirer C, Aly MS, Cassiman JJ, Eeckhout Y, Rousseau G.（1992）, The gene for tissue inhibitor of metalloproteinases-2 is localized on human chromosome arm 17q25. Genomics ,14 ; 782-784.
Deshimaru M, Yoshimi S, Shioi S, Terada S.（2004）, Multigene family for Bowman-Birk type proteinase inhibitors of wild soja and soybean: the presence of two BBI-A genes and pseudogenes. Bioscience, biotechnology, and biochemistry, 68 ; 1279-1286.
Dittmann K, Toulany M, Classen J, Heinrich V, Milas L, Rodemann HP.（2005）, Selective Radioprotection of Normal Tissues by Bowman-Birk Proteinase Inhibitor (BBI) in Mice. Strahlenther Onkol , 181; 191-196.
Duong Van Huyen JP, Viltard M, Nehiri T, Freund N, Bélair MF, Martinerie C, Lelongt B, Bruneval P, Lelièvre-Pégorier M.（2007）, Expression of matrix metalloproteinases MMP-2 and MMP-9 is altered during nephrogenesis in fetuses from diabetic rats. Laboratory Investigation , 87; 680-689.
Greene J, Wang M, Liu YE, Raymond LA, Rosen C, Shi YE.（1996）, Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. The Journal of Biological Chemistry , 271; 30375-30380.
Grossi F, Aita M, Follador A, Defferrari C, Brianti A, Sinaccio G, Belvedere O.（2007）, Sequential, alternating, and maintenance/ consolidation chemotherapy in advanced non-small cell lung cancer. Oncologist , 12; 451-464.
He Y, Liu XD, Chen ZY, Zhu J, Xiong Y, Li K, Dong JH, Li X.（2007）,Interaction between cancer cells and stromal fibroblasts is required for activation of the uPAR-uPA-MMP-2 cascade in pancreatic cancer metastasis. Clinical Cancer Research , 13;3115-3124.
Henderson N, Markwick LJ, Elshaw SR, Freyer AM, Knox AJ, Johnson SR.（2007）, American journal of physiology. Lung Cellular and Molecular Physiology, 292;L1030-1038.
Hofmann GE, Glatstein I, Schatz F, Heller D, Deligdisch L（1994）, Immunohistochemical localization of urokinase-type plasminogen activator and the plasminogen activator inhibitors 1 and 2 in early human implantation sites. American Journal of Obstetrics and Gynecology , 170; 671-676.
Hoikkala S, Pääkkö P, Soini Y, Mäkitaro R, Kinnula V, Turpeenniemi-Hujanen T.（2006）, Tissue MMP-2 and MMP-9 are better prognostic factors than serum MMP-2/TIMP-2--complex or TIMP-1 in stage I-III lung carcinoma. Cancer Letters , 236; 125-132.
Hornebeck W, Lambert E, Petitfrère E, Bernard P.（2005）, Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression. Biochimie , 87; 377-383.
Hsieh YS, Chu SC, Yang SF, Chen PN, Liu YC, Lu KH.（2007）, Silibinin suppresses human osteosarcoma MG-63 cell invasion by inhibiting the ERK-dependent c-Jun/AP-1 induction of MMP-2. Carcinogenesis , 28; 977-987.
Hsieh YS, Yang SF, Chu SC, Chen PN, Chou MC, Hsu MC, Lu KH.（2004）, Expression changes of gelatinases in human osteoarthritic knees and arthroscopic debridement. Arthroscopy ,20; 482-488.
Huh MI, Lee YM, Seo SK, Kang BS, Chang Y, Lee YS, Fini ME, Kang SS, Jung JC.（2007）, Roles of MMP/TIMP in regulating matrix swelling and cell migration during chick corneal development. Journal of Cellular Bioche Mistry 12; [Epub ahead of print]
Hung CH, Lee MC, Lin JY.（1994）, Inactivation of Acacia confusa trypsin inhibitor by site-specific mutagenesis. FEBS Lett , 353; 312-314.
Iniesta P, Morán A, De Juan C, Gómez A, Hernando F, García-Aranda C, Frías C, Díaz-López A, Rodríguez-Jiménez FJ, Balibrea JL, Benito M.（2007）, Biological and clinical significance of MMP-2, MMP-9, TIMP-1 and TIMP-2 in non-small cell lung cancer. Oncology Reports , 17; 217-223.
Jee BK, Park KM, Surendran S, Lee WK, Han CW, Kim YS, Lim Y.（2006）, KAI1/CD82 suppresses tumor invasion by MMP9 inactivation via TIMP1 up-regulation in the H1299 human lung carcinoma cell line. Biochemical and Biophysical Rresearch Communications, 342; 655-661.
Johnsen M, Lund LR, Rømer J, Almholt K, Danø K.（1998）, Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Current Opinion in Cell Biology , 10; 667-671.
Johnson MD, Kim HR, Chesler L, Tsao-Wu G, Bouck N, Polverini PJ.（1994）, Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. Journal of Cellular Physiology , 160; 194-202.
Kabir-Salmani M, Shimizu Y, Sakai K, Iwashita M.（2005）, Posttranslational modifications of decidual IGFBP-1 by steroid hormones in vitro. Molecular Human Reproduction ,11; 667-671.
Kajanne R, Miettinen P, Mehlem A, Leivonen SK, Birrer M, Foschi M, Kähäri VM, Leppä S.（2007）, EGF-R regulates MMP function in fibroblasts through MAPK and AP-1 pathways. Journal of Cellular Physiology ,212; 489-497.
Kennedy, A. R. (1998),. The Bowman-Birk inhibitor from soybeans as an anticarcinogenic agent. The American Journal of Clinical Nutrition , 68; 1406S-1412S.
Kennedy AR, Billings PC, Wan XS, Newberne PM.（2002）, Effects of Bowman-Birk inhibitor on rat colon carcinogenesis. Nutrition and Cancer , 43; 174-186.
Kennedy AR, Kritchevsky D, Shen WC.（2003）, Effects of spermine-conjugated Bowman-Birk inhibitor (spermine-BBI) on carcinogenesis and cholesterol biosynthesis in mice. Pharmaceutical Research , 20; 1908-1910.
Kennedy CW, Donahue JJ, Wan XS.（1996）, Effects of the Bowman-Birk protease inhibitor on survival of fibroblasts and cancer cells exposed to radiation and cis-platinum. Nutrition and Cancer ,26; 209-217.
Kim D, Kim S, Koh H, Yoon SO, Chung AS, Cho KS, Chung J.（2001）, Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. The FASEB Journal , 15; 1953-1962.
Kim ES, Sohn YW, Moon A. (2007), TGF-beta-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Letters , 252; 147-156.
Kong D, Li Y, Wang Z, Banerjee S, Sarkar FH. (2007), Inhibition of angiogenesis and invasion by 3,3''-diindolylmethane is mediated by the nuclear factor-kappaB downstream target genes MMP-9 and uPA that regulated bioavailability of vascular endothelial growth factor in prostate cancer. Cancer Research, 67 ; 3310-3319.
Kortt, A. A. and M. A. Jermyn (1981), Acacia proteinase inhibitors. Purification and properties of the trypsin inhibitors from Acacia elata seed. European Journal of Biochemistry , 115; 551-557.
Koskivirta I, Rahkonen O, Mäyränpää M, Pakkanen S, Husheem M, Sainio A, Hakovirta H, Laine J, Jokinen E, Vuorio E, Kovanen P, Järveläinen H. Koskivirta I, Rahkonen O, Mäyränpää M, Pakkanen S, Husheem M, Sainio A, Hakovirta H, Laine J, Jokinen E, Vuorio E, Kovanen P, Järveläinen H. (2006), Tissue inhibitor of metalloproteinases 4 (TIMP4) is involved in inflammatory processes of human cardiovascular pathology. Histochemistry and Cell Biology , 126; 335-342.
Kubiatowski T, Jang T, Lachyankar MB, Salmonsen R, Nabi RR, Quesenberry PJ, Litofsky NS, Ross AH, Recht LD. (2001), Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas. Journal of Neurosurgery , 95; 480-488.
Lee SK, Chun HK, Yang JY, Han DC, Son KH, Kwon BM. (2007), Inhibitory effect of obovatal on the migration and invasion of HT1080 cells via the inhibition of MMP-2. Bioorganic and Medicinal Chemistry, 15 ; 4085-4090.
Lee SO, Jeong YJ, Im HG, Kim CH, Chang YC, Lee IS. (2007), Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells. Biochemical and Biophysical Research Communications, 354 ; 165-171.
Lee SR, Guo SZ, Scannevin RH, Magliaro BC, Rhodes KJ, Wang X, Lo EH. (2007), Induction of matrix metalloproteinase, cytokines and chemokines in rat cortical astrocytes exposed to plasminogen activators. Neuroscience Letters , 417; 1-5.
Liabakk NB, Talbot I, Smith RA, Wilkinson K, Balkwill F. (1996), Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Research ,56; 190-196.
Liang KC, Lee CW, Lin WN, Lin CC, Wu CB, Luo SF, Yang CM. (2007), Interleukin-1beta induces MMP-9 expression via p42/p44 MAPK, p38 MAPK, JNK, and nuclear factor-kappaB signaling pathways in human tracheal smooth muscle cells. Journal of Cellular Physiology , 211; 759-70.
Lin JY, Chu SC, Wu HC, Hsieh YS. (1991), Trypsin inhibitor from the seeds of Acacia confusa. Journal of Biochemistry (Tokyo), 110; 879-83.
Luo, J. (2006), Role of matrix metalloproteinase-2 in ethanol-induced invasion by breast cancer cells. Journal of Gastroenterology and Hepatology, 21; S65-S68.
Ma Z, Dong A, Kong M, Qian J. (2007), Silencing of the type 1 insulin-like growth factor receptor increases the sensitivity to apoptosis and inhibits invasion in human lung adenocarcinoma A549 cells. Cellular and Molecular Biology Letters,〔Epub ahead of print〕.
Maffucci, T. and M. Falasca (2007), Phosphoinositide 3-kinase- dependent regulation of phospholipase Cgamma. Biochemical Society Transactions , 35; 229-230.
Malik, M. T. and S. S. Kakar (2006), Regulation of angiogenesis and invasion by human Pituitary tumor transforming gene (PTTG) through increased expression and secretion of matrix metalloproteinase-2 (MMP-2). Molecular Cancer, 5 ; 61.
Martin EL, Truscott EA, Bailey TC, Leco KJ, McCaig LA, Lewis JF, Veldhuizen RA. (2007), Lung mechanics in the TIMP3 null mouse and its response to mechanical ventilation. Perimental Lung Research, 33; 99-113.
Massi G, Bruscalupi G, Auconi P. (1982), Serum protease inhibitory capacity. (Recent knowledge on alpha 1-antitrypsin deficiency). La Ricerca in Clinica e in Laboratorio, 12; 449-458.
Messadi DV, Billings P, Shklar G, Kennedy AR. (1986), Inhibition of oral carcinogenesis by a protease inhibitor. Journal of the National Cancer Institute ,76; 447-452.
Moral MA, Khurdayan VK, Bozzo J. (2006), Chronicles in drug discovery. Drug News and Perspectives ,19; 485-489.
Mosmann, T. (1983), Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Journal of Immunological Methods, 65; 55-63.
Murphy, G. and A. J. Docherty (1992), The matrix metalloproteinases and their inhibitors. American Journal of Respiratory Cell and Molecular Biology ,7; 120-125.
Murphy G, Reynolds JJ, Hembry RM. (1989), Metalloproteinases and cancer invasion and metastasis. Journal International du Cancer ,44; 757-760.
Nabeshima K, Inoue T, Shimao Y, Sameshima T. (2002), Matrix metalloproteinases in tumor invasion: role for cell migration. Pathology International ,52; 255-264.
Nagase, H. (1997), Activation mechanisms of matrix metalloproteinases. Biological Chemistry ,378; 151-160.
Nagase, H. and J. F. Woessner, Jr. (1999), Matrix metalloproteinases. The Journal of Biological Chemistry ,274; 21491-21494.
Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. (2000), Matrix metalloproteinases: biologic activity and clinical implications. Journal of Clinical Oncology ,18; 1135-1149.
Odani S, Odani S, Ono T, Ikenaka T. (1979), Proteinase inhibitors from a mimosoideae legume, Albizzia julibrissin. Homologues of soybean trypsin inhibitor (Kunitz). The Journal of Biochemistry (Tokyo), 86; 1795-1805.
Oreffo VI, Billings PC, Kennedy AR, Witschi H. (1991), Acute effects of the Bowman-Birk protease inhibitor in mice. Toxicology, 69; 165-176.
Palanki, M. S. (2002), Inhibitors of AP-1 and NF-kappa B mediated transcriptional activation: therapeutic potential in autoimmune diseases and structural diversity. Current Medicinal Chemistry , 9; 219-227.
Pan, M. R. and W. C. Hung (2002), Nonsteroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 via suppression of the ERK/Sp1-mediated transcription. The Journal of Biological Chemistry, 277; 32775-32780.
Pappot H, Pedersen AN, Brünner N, Christensen IJ. (2006), The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) in pulmonary adenocarcinoma: relation to prognosis. Lung Cancer, 51; 193-200.
Park BC, Thapa D, Lee YS, Kwak MK, Lee ES, Choi HG, Yong CS, Kim JA. (2007), 1-furan-2-yl-3-pyridin-2-yl-propenone inhibits the invasion and migration of HT1080 human fibrosarcoma cells through the inhibition of proMMP-2 activation and down regulation of MMP-9 and MT1-MMP. European Journal of Pharmacology , 567; 193-197.
Park JM, Kim A, Oh JH, Chung AS (2007), Methylseleninic acid inhibits PMA-stimulated pro-MMP-2 activation mediated by MT1-MMP expression and further tumor invasion through suppression of NF-kappaB activation. Carcinogenesis , 28; 837-847.
Philip S, Bulbule A, Kundu GC. (2001), Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells. The Journal of Biological Chemistry , 276; 44926-44935.
Philip S, Bulbule A, Kundu GC. (2004), Matrix metalloproteinase-2: mechanism and regulation of NF-kappaB-mediated activation and its role in cell motility and ECM-invasion. Glycoconjugate Journal , 21; 429-441.
Rollin J, Régina S, Vourc''h P, Iochmann S, Bléchet C, Reverdiau P, Gruel Y. (2007), Influence of MMP-2 and MMP-9 promoter polymorphisms on gene expression and clinical outcome of non-small cell lung cancer. Lung Cancer , 56; 273-280.
Romer J, Bugge TH, Pyke C, Lund LR, Flick MJ, Degen JL, Dano K. (1996), Impaired wound healing in mice with a disrupted plasminogen gene. Naturalium Medicinalium, 2; 287-292.
Sato, H. (2006), Tumor metastasis and MMP inhibitor. Clinical Calcium, 16; 621- 626.
Shin Y, Yoon SH, Choe EY, Cho SH, Woo CH, Rho JY, Kim JH. (2007), PMA-induced up-regulation of MMP-9 is regulated by a PKCalpha-NF-kappaB cascade in human lung epithelial cells. Experimental and Molecular Medicine, 39 ; 97-105.
Shofuda K, Moriyama K, Nishihashi A, Higashi S, Mizushima H, Yasumitsu H, Miki K, Sato H, Seiki M, Miyazaki K (1998), Role of tissue inhibitor of metalloproteinases-2 (TIMP-2) in regulation of pro-gelatinase A activation catalyzed by membrane-type matrix metalloproteinase-1 (MT1-MMP) in human cancer cells. The Journal of Biochemistry (Tokyo), 124; 462-470.
Speake WJ, Dean RA, Kumar A, Morris TM, Scholefield JH, Watson SA. (2005), Radiation induced MMP expression from rectal cancer is short lived but contributes to in vitro invasion. European Journal of Surgical Oncology ,31; 869-874.
Stetler-Stevenson WG, Brown PD, Onisto M, Levy AT, Liotta LA. (1990), Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. The Journal of Biological Chemistry, 265; 13933-13938.
Stetler-Stevenson, W. G. and D. W. Seo (2005), TIMP-2: an endogenous inhibitor of angiogenesis. Trends in Molecular Medicine ,11; 97-103.
Sun HW, Li CJ, Chen HQ, Lin HL, Lv HX, Zhang Y, Zhang M (2007), Involvement of integrins, MAPK, and NF-kappaB in regulation of the shear stress-induced MMP-9 expression in endothelial cells. Biochemical and Biophysical Research Communications , 353; 152-158.
Tsai, S. J. (2007), The P11, tPA/plasminogen system and brain-derived neurotrophic factor: Implications for the pathogenesis of major depression and the therapeutic mechanism of antidepressants. Medical Hypotheses , 68; 180-183.
Tung YT, Wu JH, Kuo YH, Chang ST. (2007), Antioxidant activities of natural phenolic compounds from Acacia confusa bark. Bioresource Technology, 98; 1120-1123.
Wang H, Zhang Y, Heuckeroth RO.. (2007), PAI-1 deficiency reduces liver fibrosis after bile duct ligation in mice through activation of tPA. FEBS Letters , 581 ; 3098-3104.
Wang X, Mori T, Jung JC, Fini ME, Lo EH. (2002), Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase. Journal of Neurotrauma , 19 ; 615-625.
Wang, Y. and Y. Jin (2007), Research progress on epigenetics of lung cancer. Journal of Hygiene Research, 36 ; 109-111.
Welch DR, Sakamaki T, Pioquinto R, Leonard TO, Goldberg SF, Hon Q, Erikson RL, Rieber M, Rieber MS, Hicks DJ, Bonventre JV, Alessandrini A. (2000), Transfection of constitutively active mitogen-activated protein/extracellular signal-regulated kinase kinase confers tumorigenic and metastatic potentials to NIH3T3 cells. Cancer Research, 60 ; 1552-1556.
Westermarck, J. and V. M. Kahari (1999), Regulation of matrix metalloproteinase expression in tumor invasion. The FASEB Journa l, 13 ; 781-792.
Wick M, Bürger C, Brüsselbach S, Lucibello FC, Müller R. (1994), A novel member of human tissue inhibitor of metalloproteinases (TIMP) gene family is regulated during G1 progression, mitogenic stimulation, differentiation, and senescence. The Journal of Biological Chemistry ,269 ; 18953-18960.
Woessner, J. F., Jr. (1991), Matrix metalloproteinases and their inhibitors in connective tissue remodeling. The FASEB Journal, 5 ; 2145-2154.
Wu YP, Siao CJ, Lu W, Sung TC, Frohman MA, Milev P, Bugge TH, Degen JL, Levine JM, Margolis RU, Tsirka SE (2000), The tissue plasminogen activator (tPA)/plasmin extracellular proteolytic system regulates seizure-induced hippocampal mossy fiber outgrowth through a proteoglycan substrate. The Journal of Cell Biology , 148; 1295-1304.
Xie P, Browning DD, Hay N, Mackman N, Ye RD (2000), Activation of NF-kappa B by bradykinin through a Galpha(q)- and Gbeta gamma-dependent pathway that involves phosphoinositide 3-kinase and Akt. The Journal of Biological Chemistry ,275; 24907-24914.
Yang, T. T. and S. P. Hawkes (1992),. Role of the 21-kDa protein TIMP-3 in oncogenic transformation of cultured chicken embryo fibroblasts. The FASEB Journal , 89; 10676-10680.
Yavelow J, Finlay TH, Kennedy AR, Troll W. (1983), Bowman-Birk soybean protease inhibitor as an anticarcinogen. Cancer Research ,43; 2454s-2459s.
Yeh MW, Rougier JP, Park JW, Duh QY, Wong M, Werb Z, Clark OH. (2006). Differentiated thyroid cancer cell invasion is regulated through epidermal growth factor receptor-dependent activation of matrix metalloproteinase (MMP)-2/gelatinase A. Endocrine Related Cancer ,13; 1173-1183.
Yoshida M, Korfhagen TR, Whitsett JA (2001), Surfactant protein D regulates NF-kappa B and matrix metalloproteinase production in alveolar macrophages via oxidant-sensitive pathways. The Journal of Immunology, 166; 7514-7519.
Yoshioka I, Tsuchiya Y, Aozuka Y, Onishi Y, Sakurai H, Koizumi K, Tsukada K, Saiki I. (2005), Urinary trypsin inhibitor suppresses surgical stress-facilitated lung metastasis of murine colon 26-L5 carcinoma cells. Anticancer Research , 25; 815-820.
Yu HZ, Li ZP, Li SG, Wu CM (2005), Correlations of serous levels of matrix metalloproteinases (MMP-2 and MMP-9) to invasion and metastasis of papillary thyroid carcinoma. Ai Zheng, 24; 740-742.
Zhang D, Bar-Eli M, Meloche S, Brodt P. (2004), Dual regulation of MMP-2 expression by the type 1 insulin-like growth factor receptor: the phosphatidylinositol 3-kinase/Akt and Raf/ERK pathways transmit opposing signals. The Journal of Biological Chemistry, 279; 19683-19690.
Zhang, J. D. and Y. Zhang (2005), Interregulation of VEGF/R endostatin and MMP in the angiogenesis of hematologic malignancies. Journal of Experimental Hematologyy ,13; 1145-1150.
Zhang Q, Adiseshaiah P, Reddy SP. (2005), Matrix metalloproteinase / epidermal growth factor receptor / mitogen - activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. American Journal of Rrespiratory Cell and Molecular Biology ,32; 72-81.