請用此 Handle URI 來引用此文件：
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22660完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林淑華 | |
| dc.contributor.author | Yu-Chen Hsu | en |
| dc.contributor.author | 徐玉真 | zh_TW |
| dc.date.accessioned | 2021-06-08T04:23:47Z | - |
| dc.date.copyright | 2010-09-13 | |
| dc.date.issued | 2010 | |
| dc.date.submitted | 2010-06-25 | |
| dc.identifier.citation | Aiken, J., Cima, L., Schloo, B., Mooney, D., Johnson, L., Langer, R., and Vacanti, J. P. (1990). Studies in rat liver perfusion for optimal harvest of hepatocytes. J Pediatr Surg 25, 140-144; discussion 144-145.
Auerbach, R., Lu, W. C., Pardon, E., Gumkowski, F., Kaminska, G., and Kaminski, M. (1987). Specificity of adhesion between murine tumor cells and capillary endothelium: an in vitro correlate of preferential metastasis in vivo. Cancer Res 47, 1492-1496. Bergoffen, J., Scherer, S. S., Wang, S., Scott, M. O., Bone, L. J., Paul, D. L., Chen, K., Lensch, M. W., Chance, P. F., and Fischbeck, K. H. (1993). Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science 262, 2039-2042. Berthoud, V. M., Minogue, P. J., Laing, J. G., and Beyer, E. C. (2004). Pathways for degradation of Connexins and gap junctions. Cardiovasc Res 62, 256-267. Bladt, F., Riethmacher, D., Isenmann, S., Aguzzi, A., and Birchmeier, C. (1995). Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 376, 768-771. Boccaccio, C., Ando, M., Tamagnone, L., Bardelli, A., Michieli, P., Battistini, C., and Comoglio, P. M. (1998). Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 391, 285-288. Boitano, S., Dirksen, E. R., and Sanderson, M. J. (1992). Intercellular propagation of calcium waves mediated by inositol trisphosphate. Science 258, 292-295. Boros, P., and Miller, C. M. (1995). Hepatocyte growth factor: a multifunctional cytokine. Lancet 345, 293-295. Bussolino, F., Di Renzo, M. F., Ziche, M., Bocchietto, E., Olivero, M., Naldini, L., Gaudino, G., Tamagnone, L., Coffer, A., and Comoglio, P. M. (1992). Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119, 629-641. Carnaud, C., Hoch, B., and Trainin, N. (1974). Influence of immunologic competence of the host on metastases induced by the 3LL Lewis tumor in mice. J Natl Cancer Inst 52, 395-399. Chambers, A. F., and Matrisian, L. M. (1997). Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89, 1260-1270. Chen, C. H., Su, K. Y., Tao, M. H., Lin, S. W., Su, Y. H., Tsai, Y. C., Cheng, K. C., Jeng, Y. M., and Sheu, J. C. (2006). Decreased expressions of hepsin in human hepatocellular carcinomas. Liver Int 26, 774-780. Christoffels, V. M., Sassi, H., Ruijter, J. M., Moorman, A. F., Grange, T., and Lamers, W. H. (1999). A mechanistic model for the development and maintenance of portocentral gradients in gene expression in the liver. Hepatology 29, 1180-1192. Coman, D. R., de, L. R., and Mcc, U. M. (1951). Studies on the mechanisms of metastasis; the distribution of tumors in various organs in relation to the distribution of arterial emboli. Cancer Res 11, 648-651. Contreras, J. E., Sanchez, H. A., Veliz, L. P., Bukauskas, F. F., Bennett, M. V., and Saez, J. C. (2004). Role of Connexin-based gap junction channels and hemichannels in ischemia-induced cell death in nervous tissue. Brain Res Brain Res Rev 47, 290-303. Date, K., Matsumoto, K., Kuba, K., Shimura, H., Tanaka, M., and Nakamura, T. (1998). Inhibition of tumor growth and invasion by a four-kringle antagonist (HGF/NK4) for hepatocyte growth factor. Oncogene 17, 3045-3054. Date, K., Matsumoto, K., Shimura, H., Tanaka, M., and Nakamura, T. (1997). HGF/NK4 is a specific antagonist for pleiotrophic actions of hepatocyte growth factor. FEBS Lett 420, 1-6. Dbouk, H. A., Mroue, R. M., El-Sabban, M. E., and Talhouk, R. S. (2009). Connexins: a myriad of functions extending beyond assembly of gap junction channels. Cell Commun Signal 7, 4. De Vooght, V., Vanoirbeek, J. A., Haenen, S., Verbeken, E., Nemery, B., and Hoet, P. H. (2009). Oropharyngeal aspiration: an alternative route for challenging in a mouse model of chemical-induced asthma. Toxicology 259, 84-89. Dhanasekaran, S. M., Barrette, T. R., Ghosh, D., Shah, R., Varambally, S., Kurachi, K., Pienta, K. J., Rubin, M. A., and Chinnaiyan, A. M. (2001). Delineation of prognostic biomarkers in prostate cancer. Nature 412, 822-826. Ding, L., Sunamura, M., Kodama, T., Yamauchi, J., Duda, D. G., Shimamura, H., Shibuya, K., Takeda, K., and Matsuno, S. (2001). In vivo evaluation of the early events associated with liver metastasis of circulating cancer cells. Br J Cancer 85, 431-438. Eiberger, J., Degen, J., Romualdi, A., Deutsch, U., Willecke, K., and Sohl, G. (2001). Connexin genes in the mouse and human genome. Cell Commun Adhes 8, 163-165. Ewing, J. (1928). Neoplastic Diseases 6edn: W. B. Saunders, Philadelphia.). Farquhar, M. G., and Palade, G. E. (1963). Junctional complexes in various epithelia. J Cell Biol 17, 375-412. Fidler, I. J. (1970). Metastasis: guantitative analysis of distribution and fate of tumor embolilabeled with 125 I-5-iodo-2'-deoxyuridine. J Natl Cancer Inst 45, 773-782. Fidler, I. J. (2001). Seed and soil revisited: contribution of the organ microenvironment to cancer metastasis. Surg Oncol Clin N Am 10, 257-269, vii-viiii. Fidler, I. J. (2003). The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer 3, 453-458. Fidler, I. J., and Kripke, M. L. (1977). Metastasis results from preexisting variant cells within a malignant tumor. Science 197, 893-895. Fixman, E. D., Holgado-Madruga, M., Nguyen, L., Kamikura, D. M., Fournier, T. M., Wong, A. J., and Park, M. (1997). Efficient cellular transformation by the Met oncoprotein requires a functional Grb2 binding site and correlates with phosphorylation of the Grb2-associated proteins, Cbl and Gab1. J Biol Chem 272, 20167-20172. Gabriel, H. D., Jung, D., Butzler, C., Temme, A., Traub, O., Winterhager, E., and Willecke, K. (1998). Transplacental uptake of glucose is decreased in embryonic lethal Connexin26-deficient mice. J Cell Biol 140, 1453-1461. Gaietta, G., Deerinck, T. J., Adams, S. R., Bouwer, J., Tour, O., Laird, D. W., Sosinsky, G. E., Tsien, R. Y., and Ellisman, M. H. (2002). Multicolor and electron microscopic imaging of Connexin trafficking. Science 296, 503-507. Gassmann, P., Hemping-Bovenkerk, A., Mees, S. T., and Haier, J. (2009). Metastatic tumor cell arrest in the liver-lumen occlusion and specific adhesion are not exclusive. Int J Colorectal Dis 24, 851-858. Gebhardt, R., and Mecke, D. (1983). Heterogeneous distribution of glutamine synthetase among rat liver parenchymal cells in situ and in primary culture. EMBO J 2, 567-570. Giavazzi, R., Jessup, J. M., Campbell, D. E., Walker, S. M., and Fidler, I. J. (1986). Experimental nude mouse model of human colorectal cancer liver metastases. J Natl Cancer Inst 77, 1303-1308. Graziani, A., Gramaglia, D., Cantley, L. C., and Comoglio, P. M. (1991). The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. J Biol Chem 266, 22087-22090. Graziani, A., Gramaglia, D., dalla Zonca, P., and Comoglio, P. M. (1993). Hepatocyte growth factor/scatter factor stimulates the Ras-guanine nucleotide exchanger. J Biol Chem 268, 9165-9168. Greene, H. S., and Harvey, E. K. (1964). The Relationship between the Dissemination of Tumor Cells and the Distribution of Metastases. Cancer Res 24, 799-811. Guipponi, M., Tan, J., Cannon, P. Z., Donley, L., Crewther, P., Clarke, M., Wu, Q., Shepherd, R. K., and Scott, H. S. (2007). Mice deficient for the type II transmembrane serine protease, TMPRSS1/hepsin, exhibit profound hearing loss. Am J Pathol 171, 608-616. Hailfinger, S., Jaworski, M., Braeuning, A., Buchmann, A., and Schwarz, M. (2006). Zonal gene expression in murine liver: lessons from tumors. Hepatology 43, 407-414. Hart, I. R., and Fidler, I. J. (1980). Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res 40, 2281-2287. Herter, S., Piper, D. E., Aaron, W., Gabriele, T., Cutler, G., Cao, P., Bhatt, A. S., Choe, Y., Craik, C. S., Walker, N., et al. (2005). Hepatocyte growth factor is a preferred in vitro substrate for human hepsin, a membrane-anchored serine protease implicated in prostate and ovarian cancers. Biochem J 390, 125-136. Herve, J. C., Bourmeyster, N., and Sarrouilhe, D. (2004). Diversity in protein-protein interactions of Connexins: emerging roles. Biochim Biophys Acta 1662, 22-41. Hooper, J. D., Campagnolo, L., Goodarzi, G., Truong, T. N., Stuhlmann, H., and Quigley, J. P. (2003). Mouse matriptase-2: identification, characterization and comparative mRNA expression analysis with mouse hepsin in adult and embryonic tissues. Biochem J 373, 689-702. Hughes, D. L., Stafford, P., Hamaia, S. W., Harmer, J., Schoolmeester, A., Deckmyn, H., Farndale, R. W., Ouwehand, W. H., and Watkins, N. A. (2005). Platelet integrin alpha2 I-domain specific antibodies produced via domain specific DNA vaccination combined with variable gene phage display. Thromb Haemost 94, 1318-1326. Hujanen, E. S., and Terranova, V. P. (1985). Migration of tumor cells to organ-derived chemoattractants. Cancer Res 45, 3517-3521. Ikejima, K., Watanabe, S., Kitamura, T., Hirose, M., Miyazaki, A., and Sato, N. (1995). Hepatocyte growth factor inhibits intercellular communication via gap junctions in rat hepatocytes. Biochem Biophys Res Commun 214, 440-446. Ito, A., Morita, N., Miura, D., Koma, Y., Kataoka, T. R., Yamasaki, H., Kitamura, Y., Kita, Y., and Nojima, H. (2004). A derivative of oleamide potently inhibits the spontaneous metastasis of mouse melanoma BL6 cells. Carcinogenesis 25, 2015-2022. Itoh, H., Naganuma, S., Takeda, N., Miyata, S., Uchinokura, S., Fukushima, T., Uchiyama, S., Tanaka, H., Nagaike, K., Shimomura, T., et al. (2004). Regeneration of injured intestinal mucosa is impaired in hepatocyte growth factor activator-deficient mice. Gastroenterology 127, 1423-1435. Jeffers, M., Rong, S., and Vande Woude, G. F. (1996a). Enhanced tumorigenicity and invasion-metastasis by hepatocyte growth factor/scatter factor-met signalling in human cells concomitant with induction of the urokinase proteolysis network. Mol Cell Biol 16, 1115-1125. Jeffers, M., Rong, S., and Woude, G. F. (1996b). Hepatocyte growth factor/scatter factor-Met signaling in tumorigenicity and invasion/metastasis. J Mol Med 74, 505-513. Jungermann, K., and Katz, N. (1989). Functional specialization of different hepatocyte populations. Physiol Rev 69, 708-764. Kamimoto, M., Rung-Ruangkijkrai, T., and Iwanaga, T. (2005). Uptake ability of hepatic sinusoidal endothelial cells and enhancement by lipopolysaccharide. Biomed Res 26, 99-107. Kao, C. H., Chen, J. K., Kuo, J. S., and Yang, V. C. (1995). Visualization of the transport pathways of low density lipoproteins across the endothelial cells in the branched regions of rat arteries. Atherosclerosis 116, 27-41. Kawaida, K., Matsumoto, K., Shimazu, H., and Nakamura, T. (1994). Hepatocyte growth factor prevents acute renal failure and accelerates renal regeneration in mice. Proc Natl Acad Sci U S A 91, 4357-4361. Kawamura, S., Kurachi, S., Deyashiki, Y., and Kurachi, K. (1999). Complete nucleotide sequence, origin of isoform and functional characterization of the mouse hepsin gene. Eur J Biochem 262, 755-764. Kazama, Y., Hamamoto, T., Foster, D. C., and Kisiel, W. (1995). Hepsin, a putative membrane-associated serine protease, activates human factor VII and initiates a pathway of blood coagulation on the cell surface leading to thrombin formation. J Biol Chem 270, 66-72. Kelsell, D. P., Dunlop, J., Stevens, H. P., Lench, N. J., Liang, J. N., Parry, G., Mueller, R. F., and Leigh, I. M. (1997). Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature 387, 80-83. Kirchhofer, D., Peek, M., Lipari, M. T., Billeci, K., Fan, B., and Moran, P. (2005). Hepsin activates pro-hepatocyte growth factor and is inhibited by hepatocyte growth factor activator inhibitor-1B (HAI-1B) and HAI-2. FEBS Lett 579, 1945-1950. Klezovitch, O., Chevillet, J., Mirosevich, J., Roberts, R. L., Matusik, R. J., and Vasioukhin, V. (2004). Hepsin promotes prostate cancer progression and metastasis. Cancer Cell 6, 185-195. Kojima, T., Spray, D. C., Kokai, Y., Chiba, H., Mochizuki, Y., and Sawada, N. (2002). Cx32 formation and/or Cx32-mediated intercellular communication induces expression and function of tight junctions in hepatocytic cell line. Exp Cell Res 276, 40-51. Koval, M., Harley, J. E., Hick, E., and Steinberg, T. H. (1997). Connexin46 is retained as monomers in a trans-Golgi compartment of osteoblastic cells. J Cell Biol 137, 847-857. Kuba, K., Matsumoto, K., Ohnishi, K., Shiratsuchi, T., Tanaka, M., and Nakamura, T. (2000). Kringle 1-4 of hepatocyte growth factor inhibits proliferation and migration of human microvascular endothelial cells. Biochem Biophys Res Commun 279, 846-852. Kumar, N. M., and Gilula, N. B. (1996). The gap junction communication channel. Cell 84, 381-388. Kurachi, K., Torres-Rosado, A., and Tsuji, A. (1994). Hepsin. Methods Enzymol 244, 100-114. Lampe, P. D., and Lau, A. F. (2000). Regulation of gap junctions by phosphorylation of Connexins. Arch Biochem Biophys 384, 205-215. Lau, A. F., Kanemitsu, M. Y., Kurata, W. E., Danesh, S., and Boynton, A. L. (1992). Epidermal growth factor disrupts gap-junctional communication and induces phosphorylation of Connexin43 on serine. Mol Biol Cell 3, 865-874. Lee, S. L., Dickson, R. B., and Lin, C. Y. (2000). Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. J Biol Chem 275, 36720-36725. Leytus, S. P., Loeb, K. R., Hagen, F. S., Kurachi, K., and Davie, E. W. (1988). A novel trypsin-like serine protease (hepsin) with a putative transmembrane domain expressed by human liver and hepatoma cells. Biochemistry 27, 1067-1074. Li, F. C., Liu, Y., Huang, G. T., Chiou, L. L., Liang, J. H., Sun, T. L., Dong, C. Y., and Lee, H. S. (2009). In vivo dynamic metabolic imaging of obstructive cholestasis in mice. Am J Physiol Gastrointest Liver Physiol 296, G1091-1097. Liotta, L. A. (2001). An attractive force in metastasis. Nature 410, 24-25. Lo, C. H., Lee, S. C., Wu, P. Y., Pan, W. Y., Su, J., Cheng, C. W., Roffler, S. R., Chiang, B. L., Lee, C. N., Wu, C. W., and Tao, M. H. (2003). Antitumor and antimetastatic activity of IL-23. J Immunol 171, 600-607. Lodish, H., Berk, A., Kaiser, C. A., Krieger, M., Scott, M. P., Bretscher, A., Ploegh, H., and Matsudaira, P. (2007). Molecular cell biology, 6 edn). Lucke, B., Breedis, C., Woo, Z. P., Berwick, L., and Nowell, P. (1952). Differential growth of metastatic tumors in liver and lung; experiments with rabbit V2 carcinoma. Cancer Res 12, 734-738. Luzzi, K. J., MacDonald, I. C., Schmidt, E. E., Kerkvliet, N., Morris, V. L., Chambers, A. F., and Groom, A. C. (1998). Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153, 865-873. Madhukar, B. V., Oh, S. Y., Chang, C. C., Wade, M., and Trosko, J. E. (1989). Altered regulation of intercellular communication by epidermal growth factor, transforming growth factor-beta and peptide hormones in normal human keratinocytes. Carcinogenesis 10, 13-20. Magee, J. A., Araki, T., Patil, S., Ehrig, T., True, L., Humphrey, P. A., Catalona, W. J., Watson, M. A., and Milbrandt, J. (2001). Expression profiling reveals hepsin overexpression in prostate cancer. Cancer Res 61, 5692-5696. Maldonado, P. E., Rose, B., and Loewenstein, W. R. (1988). Growth factors modulate junctional cell-to-cell communication. J Membr Biol 106, 203-210. Manfioletti, G., Brancolini, C., Avanzi, G., and Schneider, C. (1993). The protein encoded by a growth arrest-specific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol 13, 4976-4985. Mars, W. M., Zarnegar, R., and Michalopoulos, G. K. (1993). Activation of hepatocyte growth factor by the plasminogen activators uPA and tPA. Am J Pathol 143, 949-958. Martin, P. E., Steggles, J., Wilson, C., Ahmad, S., and Evans, W. H. (2000). Targeting motifs and functional parameters governing the assembly of Connexins into gap junctions. Biochem J 349, 281-287. Matsumoto, K., Kataoka, H., Date, K., and Nakamura, T. (1998). Cooperative interaction between alpha- and beta-chains of hepatocyte growth factor on c-Met receptor confers ligand-induced receptor tyrosine phosphorylation and multiple biological responses. J Biol Chem 273, 22913-22920. Matsumoto, K., and Nakamura, T. (2003). NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer Sci 94, 321-327. Matter, K., and Balda, M. S. (2003). Signalling to and from tight junctions. Nat Rev Mol Cell Biol 4, 225-236. Miao, J., Mu, D., Ergel, B., Singavarapu, R., Duan, Z., Powers, S., Oliva, E., and Orsulic, S. (2008). Hepsin colocalizes with desmosomes and induces progression of ovarian cancer in a mouse model. Int J Cancer 123, 2041-2047. Michalopoulos, G., Houck, K. A., Dolan, M. L., and Leutteke, N. C. (1984). Control of hepatocyte replication by two serum factors. Cancer Res 44, 4414-4419. Miller, S. B., Martin, D. R., Kissane, J., and Hammerman, M. R. (1994). Hepatocyte growth factor accelerates recovery from acute ischemic renal injury in rats. Am J Physiol 266, F129-134. Miyazawa, K., Shimomura, T., Kitamura, A., Kondo, J., Morimoto, Y., and Kitamura, N. (1993). Molecular cloning and sequence analysis of the cDNA for a human serine protease reponsible for activation of hepatocyte growth factor. Structural similarity of the protease precursor to blood coagulation factor XII. J Biol Chem 268, 10024-10028. Miyazawa, K., Shimomura, T., and Kitamura, N. (1996). Activation of hepatocyte growth factor in the injured tissues is mediated by hepatocyte growth factor activator. J Biol Chem 271, 3615-3618. Mizuno, N., Kato, Y., Izumi, Y., Irimura, T., and Sugiyama, Y. (1998). Importance of hepatic first-pass removal in metastasis of colon carcinoma cells. J Hepatol 28, 865-877. Mook, O. R., Van Marle, J., Vreeling-Sindelarova, H., Jonges, R., Frederiks, W. M., and Van Noorden, C. J. (2003). Visualization of early events in tumor formation of eGFP-transfected rat colon cancer cells in liver. Hepatology 38, 295-304. Moorby, C. D., Stoker, M., and Gherardi, E. (1995). HGF/SF inhibits junctional communication. Exp Cell Res 219, 657-663. Moran, P., Li, W., Fan, B., Vij, R., Eigenbrot, C., and Kirchhofer, D. (2006). Pro-urokinase-type plasminogen activator is a substrate for hepsin. J Biol Chem 281, 30439-30446. Morris, V. L., MacDonald, I. C., Koop, S., Schmidt, E. E., Chambers, A. F., and Groom, A. C. (1993). Early interactions of cancer cells with the microvasculature in mouse liver and muscle during hematogenous metastasis: videomicroscopic analysis. Clin Exp Metastasis 11, 377-390. Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M. E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S. N., et al. (2001). Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50-56. Muramatsu, A., Iwai, M., Morikawa, T., Tanaka, S., Mori, T., Harada, Y., and Okanoue, T. (2002). Influence of transfection with Connexin 26 gene on malignant potential of human hepatoma cells. Carcinogenesis 23, 351-358. Nakamura, T., Nawa, K., and Ichihara, A. (1984). Partial purification and characterization of hepatocyte growth factor from serum of hepatectomized rats. Biochem Biophys Res Commun 122, 1450-1459. Nakamura, T., Nishizawa, T., Hagiya, M., Seki, T., Shimonishi, M., Sugimura, A., Tashiro, K., and Shimizu, S. (1989). Molecular cloning and expression of human hepatocyte growth factor. Nature 342, 440-443. Naldini, L., Tamagnone, L., Vigna, E., Sachs, M., Hartmann, G., Birchmeier, W., Daikuhara, Y., Tsubouchi, H., Blasi, F., and Comoglio, P. M. (1992). Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. EMBO J 11, 4825-4833. Naldini, L., Vigna, E., Ferracini, R., Longati, P., Gandino, L., Prat, M., and Comoglio, P. M. (1991). The tyrosine kinase encoded by the MET proto-oncogene is activated by autophosphorylation. Mol Cell Biol 11, 1793-1803. Nelles, E., Butzler, C., Jung, D., Temme, A., Gabriel, H. D., Dahl, U., Traub, O., Stumpel, F., Jungermann, K., Zielasek, J., et al. (1996). Defective propagation of signals generated by sympathetic nerve stimulation in the liver of Connexin32-deficient mice. Proc Natl Acad Sci U S A 93, 9565-9570. Nicolson, G. L. (1988). Cancer metastasis: tumor cell and host organ properties important in metastasis to specific secondary sites. Biochim Biophys Acta 948, 175-224. Nicolson, G. L., Brunson, K. W., and Fidler, I. J. (1978). Specificity of arrest, survival, and growth of selected metastatic variant cell lines. Cancer Res 38, 4105-4111. Orr, F. W., Wang, H. H., Lafrenie, R. M., Scherbarth, S., and Nance, D. M. (2000). Interactions between cancer cells and the endothelium in metastasis. J Pathol 190, 310-329. Ott, T., Jokwitz, M., Lenhard, D., Romualdi, A., Dombrowski, F., Ittrich, C., Schwarz, M., and Willecke, K. (2006). Ablation of gap junctional communication in hepatocytes of transgenic mice does not lead to disrupted cellular homeostasis or increased spontaneous tumourigenesis. Eur J Cell Biol 85, 717-728. Owen, K. A., Qiu, D., Alves, J., Schumacher, A. M., Kilpatrick, L. M., Li, J., Harris, J. L., and Ellis, V. (2010). Pericellular activation of hepatocyte growth factor by the transmembrane serine proteases matriptase and hepsin, but not by the membrane-associated protease uPA. Biochem J 426, 219-228. Paget, S. (1889). The distribution of secondary growths in cancer of the breast. . Lacent 1, 571. Pelicci, G., Giordano, S., Zhen, Z., Salcini, A. E., Lanfrancone, L., Bardelli, A., Panayotou, G., Waterfield, M. D., Ponzetto, C., Pelicci, P. G., and et al. (1995). The motogenic and mitogenic responses to HGF are amplified by the Shc adaptor protein. Oncogene 10, 1631-1638. Plotkin, L. I., Manolagas, S. C., and Bellido, T. (2002). Transduction of cell survival signals by Connexin-43 hemichannels. J Biol Chem 277, 8648-8657. Ponzetto, C., Bardelli, A., Zhen, Z., Maina, F., dalla Zonca, P., Giordano, S., Graziani, A., Panayotou, G., and Comoglio, P. M. (1994). A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77, 261-271. Poste, G. (1982). Experimental systems for analysis of the malignant phenotype. Cancer Metastasis Rev 1, 141-199. Poste, G., and Nicolson, G. L. (1980). Arrest and metastasis of blood-borne tumor cells are modified by fusion of plasma membrane vesicles from highly metastatic cells. Proc Natl Acad Sci U S A 77, 399-403. Qi, K., Qiu, H., Sun, D., Minuk, G. Y., Lizardo, M., Rutherford, J., and Orr, F. W. (2004). Impact of cirrhosis on the development of experimental hepatic metastases by B16F1 melanoma cells in C57BL/6 mice. Hepatology 40, 1144-1150. Quist, A. P., Rhee, S. K., Lin, H., and Lal, R. (2000). Physiological role of gap-junctional hemichannels. Extracellular calcium-dependent isosmotic volume regulation. J Cell Biol 148, 1063-1074. Raz, A., and Lotan, R. (1987). Endogenous galactoside-binding lectins: a new class of functional tumor cell surface molecules related to metastasis. Cancer Metastasis Rev 6, 433-452. Reading, C. L., and Hutchins, J. T. (1985). Carbohydrate structure in tumor immunity. Cancer Metastasis Rev 4, 221-260. Ribatti, D., Mangialardi, G., and Vacca, A. (2006). Stephen Paget and the 'seed and soil' theory of metastatic dissemination. Clin Exp Med 6, 145-149. Rodrigues, G. A., and Park, M. (1993). Dimerization mediated through a leucine zipper activates the oncogenic potential of the met receptor tyrosine kinase. Mol Cell Biol 13, 6711-6722. Rosen, E. M., Meromsky, L., Setter, E., Vinter, D. W., and Goldberg, I. D. (1990). Purified scatter factor stimulates epithelial and vascular endothelial cell migration. Proc Soc Exp Biol Med 195, 34-43. Ross, M. H., Lynn J. Romrell, and Kaye, G. I. (1995). Histology: a text and atlas, 3 edn: Williams & Wilkins). Russell, W. E., McGowan, J. A., and Bucher, N. L. (1984). Partial characterization of a hepatocyte growth factor from rat platelets. J Cell Physiol 119, 183-192. Saez, J. C., Connor, J. A., Spray, D. C., and Bennett, M. V. (1989). Hepatocyte gap junctions are permeable to the second messenger, inositol 1,4,5-trisphosphate, and to calcium ions. Proc Natl Acad Sci U S A 86, 2708-2712. Sai, K., Kanno, J., Hasegawa, R., Trosko, J. E., and Inoue, T. (2000). Prevention of the down-regulation of gap junctional intercellular communication by green tea in the liver of mice fed pentachlorophenol. Carcinogenesis 21, 1671-1676. Sakon, M., Monden, M., Gotoh, M., Kanai, T., Umeshita, K., Mori, T., Tsubouchi, H., and Daikuhara, Y. (1992). Hepatocyte growth factor concentrations after liver resection. Lancet 339, 818. Sato, M., Suzuki, S., and Senoo, H. (2003). Hepatic stellate cells: unique characteristics in cell biology and phenotype. Cell Struct Funct 28, 105-112. Scherbarth, S., and Orr, F. W. (1997). Intravital videomicroscopic evidence for regulation of metastasis by the hepatic microvasculature: effects of interleukin-1alpha on metastasis and the location of B16F1 melanoma cell arrest. Cancer Res 57, 4105-4110. Schmidt, C., Bladt, F., Goedecke, S., Brinkmann, V., Zschiesche, W., Sharpe, M., Gherardi, E., and Birchmeier, C. (1995). Scatter factor/hepatocyte growth factor is essential for liver development. Nature 373, 699-702. Shimomura, T., Kondo, J., Ochiai, M., Naka, D., Miyazawa, K., Morimoto, Y., and Kitamura, N. (1993). Activation of the zymogen of hepatocyte growth factor activator by thrombin. J Biol Chem 268, 22927-22932. Smedsrod, B., De Bleser, P. J., Braet, F., Lovisetti, P., Vanderkerken, K., Wisse, E., and Geerts, A. (1994). Cell biology of liver endothelial and Kupffer cells. Gut 35, 1509-1516. Sohl, G., and Willecke, K. (2003). An update on Connexin genes and their nomenclature in mouse and man. Cell Commun Adhes 10, 173-180. Somoza, J. R., Ho, J. D., Luong, C., Ghate, M., Sprengeler, P. A., Mortara, K., Shrader, W. D., Sperandio, D., Chan, H., McGrath, M. E., and Katz, B. A. (2003). The structure of the extracellular region of human hepsin reveals a serine protease domain and a novel scavenger receptor cysteine-rich (SRCR) domain. Structure 11, 1123-1131. Srikantan, V., Valladares, M., Rhim, J. S., Moul, J. W., and Srivastava, S. (2002). HEPSIN inhibits cell growth/invasion in prostate cancer cells. Cancer Res 62, 6812-6816. Steinbauer, M., Guba, M., Cernaianu, G., Kohl, G., Cetto, M., Kunz-Schughart, L. A., Geissler, E. K., Falk, W., and Jauch, K. W. (2003). GFP-transfected tumor cells are useful in examining early metastasis in vivo, but immune reaction precludes long-term tumor development studies in immunocompetent mice. Clin Exp Metastasis 20, 135-141. Takeuchi, T., Harris, J. L., Huang, W., Yan, K. W., Coughlin, S. R., and Craik, C. S. (2000). Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates. J Biol Chem 275, 26333-26342. Talhouk, R. S., Zeinieh, M. P., Mikati, M. A., and El-Sabban, M. E. (2008). Gap junctional intercellular communication in hypoxia-ischemia-induced neuronal injury. Prog Neurobiol 84, 57-76. Talmadge, J. E., and Fidler, I. J. (1982). Cancer metastasis is selective or random depending on the parent tumour population. Nature 297, 593-594. Tanimoto, H., Yan, Y., Clarke, J., Korourian, S., Shigemasa, K., Parmley, T. H., Parham, G. P., and O'Brien, T. J. (1997). Hepsin, a cell surface serine protease identified in hepatoma cells, is overexpressed in ovarian cancer. Cancer Res 57, 2884-2887. Tannock, I. F., Hill, R. P., Bristow, R. G., and Harrington, L. (2004). The Basic Science of Oncology 4 edition (August 1, 2004) edn: McGraw-Hill Professional). Temme, A., Buchmann, A., Gabriel, H. D., Nelles, E., Schwarz, M., and Willecke, K. (1997). High incidence of spontaneous and chemically induced liver tumors in mice deficient for Connexin32. Curr Biol 7, 713-716. Testa Riva, F., Serreli, S., Loy, F., and Riva, A. (2003). Junctional complex revisited by high-resolution scanning electron microscopy. Microsc Res Tech 62, 225-231. Torres-Rosado, A., O'Shea, K. S., Tsuji, A., Chou, S. H., and Kurachi, K. (1993). Hepsin, a putative cell-surface serine protease, is required for mammalian cell growth. Proc Natl Acad Sci U S A 90, 7181-7185. Tsubouchi, H., Hirono, S., Gohda, E., Nakayama, H., Takahashi, K., Sakiyama, O., Kimoto, M., Kawakami, S., Miyoshi, H., Kubozono, O., and et al. (1991a). Human hepatocyte growth factor in blood of patients with fulminant hepatic failure. I. Clinical aspects. Dig Dis Sci 36, 780-784. Tsubouchi, H., Niitani, Y., Hirono, S., Nakayama, H., Gohda, E., Arakaki, N., Sakiyama, O., Takahashi, K., Kimoto, M., Kawakami, S., and et al. (1991b). Levels of the human hepatocyte growth factor in serum of patients with various liver diseases determined by an enzyme-linked immunosorbent assay. Hepatology 13, 1-5. Tsuji, A., Torres-Rosado, A., Arai, T., Chou, S. H., and Kurachi, K. (1991a). Characterization of hepsin, a membrane bound protease. Biomed Biochim Acta 50, 791-793. Tsuji, A., Torres-Rosado, A., Arai, T., Le Beau, M. M., Lemons, R. S., Chou, S. H., and Kurachi, K. (1991b). Hepsin, a cell membrane-associated protease. Characterization, tissue distribution, and gene localization. J Biol Chem 266, 16948-16953. Turner, G. A. (1982). Surface properties of the metastatic cell. Invasion Metastasis 2, 197-216. Uehara, Y., Minowa, O., Mori, C., Shiota, K., Kuno, J., Noda, T., and Kitamura, N. (1995). Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 373, 702-705. Uehara, Y., Mori, C., Noda, T., Shiota, K., and Kitamura, N. (2000). Rescue of embryonic lethality in hepatocyte growth factor/scatter factor knockout mice. Genesis 27, 99-103. Vu, T. K., Liu, R. W., Haaksma, C. J., Tomasek, J. J., and Howard, E. W. (1997). Identification and cloning of the membrane-associated serine protease, hepsin, from mouse preimplantation embryos. J Biol Chem 272, 31315-31320. Wang, H. H., McIntosh, A. R., Hasinoff, B. B., Rector, E. S., Ahmed, N., Nance, D. M., and Orr, F. W. (2000). B16 melanoma cell arrest in the mouse liver induces nitric oxide release and sinusoidal cytotoxicity: a natural hepatic defense against metastasis. Cancer Res 60, 5862-5869. Wang, H. H., Nance, D. M., and Orr, F. W. (1999). Murine hepatic microvascular adhesion molecule expression is inducible and has a zonal distribution. Clin Exp Metastasis 17, 149-155. Weibel, E. (1973). Stereological techniques for electron microscope. , ( New York Van Nostrand-Reinhold). Weidner, K. M., Arakaki, N., Hartmann, G., Vandekerckhove, J., Weingart, S., Rieder, H., Fonatsch, C., Tsubouchi, H., Hishida, T., Daikuhara, Y., and et al. (1991). Evidence for the identity of human scatter factor and human hepatocyte growth factor. Proc Natl Acad Sci U S A 88, 7001-7005. Weidner, K. M., Di Cesare, S., Sachs, M., Brinkmann, V., Behrens, J., and Birchmeier, W. (1996). Interaction between Gab1 and the c-Met receptor tyrosine kinase is responsible for epithelial morphogenesis. Nature 384, 173-176. Weiss, L. (1992). Comments on hematogenous metastatic patterns in humans as revealed by autopsy. Clin Exp Metastasis 10, 191-199. Wisse, E. (1977). Ultrastructure and function of Kupffer cells and other sinusoid | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/22660 | - |
| dc.description.abstract | Hepsin為第二型穿膜絲胺酸蛋白酶，以肝臟細胞的表現量最多。相關文獻指出，Hepsin可能參與肝細胞發育、受精卵著床、血液凝固機轉等過程，但分子機制尚不明確。此外Hepsin在多種癌細胞株中大量表現，尤以前列腺癌最為明顯，除可成為癌細胞的生物標記外，許多證據顯示Hepsin 可能參與癌細胞的生長與轉移，但調控方式仍不清楚。至於hepsin基因剔除小鼠因無明顯生理異常，故Hepsin生理功能尚待研究。
為探討Hepsin蛋白的生理功能，實驗室先前研究發現，進行脾臟內植入黑色素瘤細胞的癌轉移實驗，hepsin基因剔除(KO)小鼠腫瘤細胞轉移至肝臟的聚落數明顯多於野生型(WT)小鼠，且存活率亦降低。我們根據腫瘤細胞發生轉移的過程與影響腫瘤細胞聚落形成的相關原因設計實驗，逐步排除了hepsin基因剔除小鼠可能的異常。同時，經由不同時間點的觀察，發現自脾臟內植入的黑色素瘤細胞或不同直徑的綠色螢光微球體均易留滯於hepsin基因剔除小鼠肝組織。經過穿透式電子顯微鏡及多光子活體內顯微鏡(multiphoton intravital microscope)觀察後，推測易留滯情形是由於hepsin基因剔除小鼠的肝細胞體積變大，造成血管竇直徑較野生型窄所造成。 根據目前實驗結果推測，hepsin基因剔除小鼠肝細胞體積較大，可能是由於體內缺乏Hepsin蛋白活化pro-HGF為肝細胞生長因子，使肝細胞表面間隙接合分子(gap junction)的組成蛋白Connexin 26 (Cx26)、Cx32代謝減緩後，異常堆積所造成。實驗除證明(1)hepsin基因剔除小鼠血清及肝組織中的肝細胞生長因子濃度及肝細胞生長因子受體c-met磷酸化程度均較野生型小鼠低外，也發現(2)hepsin基因剔除小鼠肝組織的Cx26、Cx32蛋白表現量及傳遞功能均較野生型好，(3) Cx26、Cx32蛋白過量表現的肝細胞株體積會變大，及(4)投予hepsin基因剔除小鼠肝細胞生長因子或投予野生型小鼠肝細胞生長因子拮抗劑NK4均能動態調節所觀察之現象。 根據肝細胞生長因子在橫膈膜發育過程十分重要，而hepsin基因剔除小鼠體內的肝細胞生長因子又濃度偏低，實驗也觀察到hepsin基因剔除小鼠橫膈膜發育異常，且導致肝臟往胸腔擠壓，影響肺功能。另外，由於肝細胞表面Cx26、Cx32蛋白表現增加，hepsin基因剔除小鼠在分離初代肝細胞時(EGTA/collagenase perfusion procedure)，細胞存活率及收得活細胞數均較野生型低的現象，可經抑制肝細胞過量表現的間隙接合分子功能，有效提升小鼠初代肝細胞分離後的存活率。 總結實驗結果具有以下重要性：(1)了解肝臟內源性Hepsin蛋白的生理功能與維持肝臟結構或體內肝細胞生長因子濃度的重要性，(2)提供生物體內Hepsin蛋白可活化pro-HGF為肝細胞生長因子的證據，(3)利用活體小鼠，直接提供器官微血管過密或肝臟血管竇過窄，會增加體循環血流中的腫瘤細胞留滯於組織器官的直接模型，且該現象能被動態調節，(4)過去文獻多偏重於Hepsin蛋白與促進癌細胞生長與轉移的關係，甚至多在探討以Hepsin抗體抑制癌轉移的可能應用，而忽略了Hepsin蛋白的生理功能；實驗證明，投予Hepsin抗體可能反而會促進腫瘤細胞轉移至肝臟的風險，需進一步釐清Hepsin蛋白各作用功能區及選擇更適合的抗體以供治療應用。 | zh_TW |
| dc.description.abstract | Hepsin, a type II transmembrane serine protease, was indicated involve in hepatocyte growth, blastocyst hatching and blood coagulation pathway. Since there is no obvious abnormality in hepsin-deficient mice, the physiological functions of Hepsin are still unknown. It has also been reported that the overexpression of Hepsin in many cancer cell lines, especially in prostate cancer. Accordindingly, beside be concerned as a biomarker in cancer, many evidences show that Hepsin may play roles in tumor proliferation and metastasis, but the mechanism is not clear so far.
To evaluate the physiological functions of Hepsin, we challenged the tumor metastasis experiment in the hepsin knockout (KO) mice and found that the isogenic tumor cells colonized more efficiently to livers in the KO mice than that in the WT mice.To investigate this mechanism, we used intrasplenic injection and time course tracing strategies showed that both melanoma cells and the different sizes of fluorescent microbeads were more preferentially trapped in hepsin KO livers. With observation through transmission electron microscope and multiphoton intravital microscope, our results showed that the preferential retention of the tumor cells in the KO mice liver is due to the altered hepatic sinusoidal architecture tortured by the enlarged hepatocytes. To delineate the mechanism responsible for the change of hepacyte sizes, we found the hepsin KO liver had increased Connexin proteins and the increased gap junctions are associated with changes of hepatocyte size. Further studies shown that hepatocyte growth factor (HGF) was associated with the expression level of Connexin proteins and the KO mice had decreased HGF in the liver microcirculation as well as in liver extracts. These observations demonstrate that hepsin involves in liver metastasis by regulating the diameter of the sinusoids and the volume of hepatocytes through its influence on HGF. Our study provides evidence showing for the first time the relationships between hepsin and HGF/SF in vivo. We also provide a direct evidence of the relationship between successful tumor metastasis and the architecture of target organs. Our findings suggest the application of hepsin protein can be potential therapeutic approach to remission of the liver metastasis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T04:23:47Z (GMT). No. of bitstreams: 1 ntu-99-F90424019-1.pdf: 11996698 bytes, checksum: 32cdbb692b59f4e31b6e9a6e6bb6c40c (MD5) Previous issue date: 2010 | en |
| dc.description.tableofcontents | 口試委員會審定書 I
誌謝 II 中文摘要 III 英文摘要 V 縮寫表 VII 第一章 緒論 1 1.1 HEPSIN 1 1.1.1 Hepsin基因與蛋白結構 1 1.1.2 Hepsin組織分佈與預測功能 2 1.1.3 Hepsin病理功能 3 1.2腫瘤轉移 4 1.2.1 腫瘤細胞轉移過程 5 1.2.2腫瘤細胞轉移理論演進與相關機制 5 1.3 肝臟結構與組成細胞 7 1.3.1肝臟組織結構與循環 7 1.3.2肝臟實質細胞及功能 8 1.3.3肝臟非實質細胞及功能 9 1.4 肝細胞縫隙連接分子 (GAP JUNCTIONAL PROTEINS) 10 1.4.1 接合分子蛋白 10 1.4.2 Connexin蛋白結構、connexon組成 11 1.4.3 Connexin功能與疾病關係 12 1.5 肝細胞生長因子 (HEPATOCYTE GROWTH FACTOR, HGF) 13 1.5.1 肝細胞生長因子結構及活化 13 1.5.2 肝細胞生長因子受器及下游訊息傳遞 15 1.5.3 肝細胞生長因子功能 15 1.6 論文研究動機與實驗策略 17 第二章 實驗材料與方法 19 2.1 實驗動物 19 2.2 活體小鼠內腫瘤細胞癌轉移及生長實驗 19 2.2.1腫瘤細胞培養 19 2.2.2小鼠脾臟內植入腫瘤細胞轉移實驗 19 2.2.3小鼠尾靜脈植入腫瘤細胞轉移實驗 20 2.2.4小鼠肝臟植入腫瘤細胞生長實驗 20 2.3組織病理學及組織免疫染色 20 2.3.1組織檢體處理及切片 20 2.3.2石臘切片的組織染色 (Hematoxylin and Eosin stain) 21 2.3.3石臘切片的免疫組織化學 (immunohistochemistry)染色 21 2.3.4冷凍切片的免疫組織螢光 (immunofluorescence)染色 22 2.4小鼠肝臟表現外源性蛋白 23 2.4.1 表現質體構築 23 2.4.2 Hydrohynamic DNA植入法 23 2.5 HEPSIN重組蛋白表現與純化 24 2.5.1 Hepsin重組蛋白表現質體構築 24 2.5.3 Hepsin膜外區重組蛋白穩定表現細胞株大量表現系統 25 2.5.4 Hepsin重組蛋白純化 26 2.5.5 Hepsin膜外區重組蛋白身分鑑定 26 2.5.6 西方墨點法 27 2.5.7 Hepsin膜外區重組蛋白活性測試 27 2.5.8 蛋白質膠體電泳膠片銀染色 28 2.6 抗HEPSIN蛋白單株抗體製備與抑制小鼠內源性HEPSIN蛋白實驗 28 2.6.1 DNA疫苗免疫法 (DNA vaccine) 28 2.6.2 Hepsin膜外區重組蛋白免疫法 28 2.6.3 利用酵素免疫連結法偵測抗體效價 29 2.6.4 細胞融合 29 2.6.5 抗體單株化 30 2.6.6 單株抗體製備與純化 31 2.6.7以單株抗體抑制小鼠內源性Hepsin蛋白實驗 32 2.6.8單株抗體抑制人類肝細胞株內源性Hepsin蛋白實驗 32 2.7小鼠肝臟各組成細胞分離、培養及相關實驗 33 2.7.1 小鼠肝臟竇間隙內皮細胞分離 33 2.7.2小鼠血管竇內皮細胞免疫螢光染色 34 2.7.3 黑色素瘤細胞與小鼠血管竇內皮細胞黏著作用 35 2.7.4 小鼠初代肝細胞分離及培養 36 2.7.5 小鼠初代肝細胞體積分析 36 2.7.6分離小鼠肝臟白血球 (intrahepatic leukocytes, IHLs)分離 36 2.7.7小鼠肝臟白血球細胞分群分析 37 2.8小鼠肝臟對於循環中腫瘤細胞及微球體 (MICROSPHERE)留滯能力 38 2.8.1 腫瘤細胞螢光標定 38 2.8.2肝組織留滯腫瘤細胞及微球體的數量計數 38 2.8.3肝組織留滯的腫瘤細胞自體凋亡之數量計數 39 2.9電子顯微鏡 39 2.9.1 檢體製備 39 2.9.2穿透式電子顯微鏡觀察、測量小鼠血管竇直徑 (sinusoidal diameter) 40 2.9.3 以穿透式電子顯微鏡觀察、測量小鼠肝細胞所佔面積 40 2.10.1多光子活體內顯微鏡 (MULTIPHOTON INTRAVITAL MICROSCOPE) 40 2.10.1 活體小鼠前處理 40 2.10.2 以多光子活體內顯微鏡測量小鼠血管竇直徑 (sinusoidal diameter) 41 2.10.3 以多光子活體內顯微鏡測量小鼠肝細胞面積 41 2.11小鼠肝臟MRNA及蛋白質表現分析與定量 41 2.11.1 小鼠肝臟RNA萃取 41 2.11.2 反轉錄反應 42 2.11.3 聚合酵素鏈鎖反應 (PCR) 42 2.11.4 即時定量聚合酵素連鎖反應 (Real-Time PCR PCR) 43 2.11.5 小鼠肝臟蛋白萃取 43 2.11.6 以西方墨點法分析小鼠肝臟蛋白 44 2.12間隙接合分子 (GAP JUNCTION) 蛋白相關功能分析 44 2.12.1小鼠肝臟間隙接合分子傳遞功能分析 44 2.12.2細胞過量表現間隙接合分子組成蛋白Connexin對細胞體積的影響 45 2.12.3間隙接合分子功能抑制劑對小鼠血管竇直徑、肝細胞體積的影響 46 2.12.4間隙接合分子功能抑制劑對小鼠肝細胞存活率、肝細胞體積的影響 46 2.13 小鼠內源性肝細胞生長因子測量及蛋白功能分析 47 2.13.1小鼠內源性肝細胞生長因子測量 47 2.13.2肝細胞生長因子及肝細胞生長因子拮抗劑NK4對小鼠血管竇直徑的影響 47 2.14 小鼠橫膈膜形態觀察及肺功能分析 48 2.14.1小鼠橫膈膜解剖及形態觀察 48 2.14.2小鼠肺功能分析 48 2.15 數據分析與統計 49 第三章 實驗結果 51 3.1HEPSIN蛋白與黑色素瘤細胞轉移至肝臟的抑制有關 51 3.1.1基因剔除小鼠腫瘤細胞轉移至肝臟的群落數明顯增多 51 3.1.2基因剔除小鼠肝臟表現Hepsin蛋白能減少腫瘤細胞轉移至肝臟 51 3.1.3抑制野生型小鼠內源性Hepsin蛋白能增加腫瘤細胞轉移至肝臟 52 3.1.4循環中的腫瘤細胞在基因剔除小鼠轉移至肝臟較多 52 3.1.5抑制野生型小鼠內源性Hepsin蛋白能增加循環中腫瘤細胞轉移至肝臟 53 3.1.6該現象非黑色素瘤細胞B16F1單一細胞株特有 53 3.1.7提供基因剔除小鼠soluble form Hepsin蛋白無法抑制腫瘤細胞轉移至肝臟 54 3.1.8表現soluble form Hepsin與否不影響腫瘤細胞轉移至肝臟能力 54 3.2 已初步排除促進腫瘤細胞轉移至肝臟的可能原因 55 3.2.1基因剔除小鼠肝臟釋放的細胞趨化素無明顯增加 55 3.2.1腫瘤細胞黏著於基因剔除小鼠內皮細胞能力無明顯增加 55 3.2.2基因剔除小鼠肝臟細胞外間質 (extracellular matrix)量無異常 56 3.2.3 Hepsin蛋白對腫瘤細胞黏著、降解細胞外間質無明顯影響 56 3.2.4 腫瘤細胞於基因剔除小鼠肝臟增生速度無明顯增加 56 3.2.5基因剔除小鼠肝臟對轉移腫瘤細胞清除能力無明顯異常 56 3.3基因剔除小鼠肝臟較易留滯腫瘤細胞 57 3.3.1基因剔除小鼠肝臟留滯的腫瘤細胞較多 57 3.3.2基因剔除小鼠肝臟留滯的腫瘤細胞凋亡比例無異常 58 3.3.3基因剔除小鼠肝臟留滯的螢光微球體較多 58 3.4 HEPSIN蛋白與肝臟血管竇直徑調節有關 59 3.4.1基因剔除小鼠血管竇直徑較窄 59 3.4.2基因剔除小鼠肝臟表現Hepsin蛋白能使血管竇直徑變寬 59 3.4.3抑制野生型小鼠內源性Hepsin蛋白使血管竇直徑變窄 60 3.5 HEPSIN蛋白與肝細胞體積調節有關 60 3.5.1基因剔除小鼠肝臟非實質細胞分佈及數量無異常 60 3.5.2 肝細胞是肝臟中Hepsin蛋白最主要的表現者 60 3.5.3基因剔除小鼠單顆肝細胞面積較大 61 3.5.4基因剔除小鼠肝臟表現Hepsin蛋白能使肝細胞面積變小 61 3.5.5抑制野生型小鼠內源性Hepsin蛋白使肝細胞面積變大 62 3.5.6抑制細胞內源性Hepsin蛋白使肝細胞體積變大 62 3.6 HEPSIN蛋白與肝組織間隙接合分子表現量有關 62 3.6.1基因剔除小鼠肝臟數個調控細胞體積的離子通道分佈及表現量正常 62 3.6.2基因剔除小鼠desmosomes分佈及表現量無明顯異常 63 3.6.3基因剔除小鼠肝臟間隙接合分子較多 63 3.6.4基因剔除小鼠肝臟間隙接合分子傳遞能力較好 63 3.6.5抑制野生型小鼠內源性Hepsin蛋白使肝臟間隙接合分子變多 63 3.6.6抑制細胞內源性Hepsin蛋白使細胞間隙接合分子變多 64 3.7肝組織間隙接合分子與細胞體積調節有關 64 3.7.1過量表現細胞間隙接合分子能使細胞體積變大 64 3.7.2間隙接合分子功能抑制劑能使基因剔除小鼠肝細胞面積變小 65 3.7.3間隙接合分子功能抑制劑能使基因剔除小鼠血管直徑增加 65 3.8肝細胞生長因子經由間隙接合分子調節細胞體積 65 3.8.1基因剔除小鼠體內肝細胞生長因子濃度較低 65 3.8.2抑制野生型小鼠內源性Hepsin蛋白使血清中肝細胞生長因子濃度降低 66 3.8.3投予肝細胞生長因子使基因剔除小鼠血管竇直徑變寬 66 3.8.4投予肝細胞生長因子拮抗劑NK4使野生型小鼠血管竇直徑變窄 67 3.9基因剔除小鼠肝細胞生長因子較少導致其它影響 67 3.9.1基因剔除小鼠橫膈膜發育異常 67 3.9.2基因剔除小鼠肝臟解剖位置偏高 68 3.9.3基因剔除小鼠引發氣管攣縮後氣道阻力及肺順應性異常 68 3.10間隙接合分子過量表現會降低初代肝細胞分離時存活率 68 3.10.1基因剔除小鼠初代肝細胞分離時存活率及收得活細胞數較低 68 3.10.2基因剔除小鼠初代肝細胞分離時存活率能經抑制間隙接合分子提高 69 第四章 討論 71 4.1 HEPSIN蛋白與黑色素瘤細胞轉移至肝臟的抑制關係 71 4.1.1腫瘤細胞癌轉移實驗模型及生成群落的觀察 71 4.1.2 Hepsin與腫瘤細胞轉移至肝臟的關係 73 4.2促進腫瘤細胞轉移至基因剔除小鼠肝臟的可能原因 75 4.2.1已初步排除促進腫瘤細胞轉移的可能原因 75 4.2.2轉移的腫瘤細胞留滯肝組織與聚落生成的關係 76 4.3 HEPSIN蛋白與肝細胞體積調節的關係 77 4.3.1基因剔除小鼠血管竇變窄源自肝細胞體積較大 77 4.3.2已初步排除造成基因剔除小鼠肝細胞變大的可能原因 78 4.3.3肝組織間隙接合分子與細胞體積的關係 79 4.4 HEPSIN蛋白與肝細胞生長因子關係 80 4.4.1基因剔除小鼠體內肝細胞生長因子濃度較低 80 4.4.2細胞生長因子經由間隙接合分子調節細胞體積。 81 4.5基因剔除小鼠肝細胞生長因子較少導致其它影響 82 4.5.1基因剔除小鼠橫膈膜發育異常。 82 4.5.2基因剔除小鼠肝細胞間隙接合分子功能。 83 第五章 實驗結果與展望 85 參考文獻 87 圖 101 表 168 | |
| dc.language.iso | zh-TW | |
| dc.title | 利用基因剔除小鼠探討Hepsin的生理功能 | zh_TW |
| dc.title | Investigation of the physiological functions of Hepsin using gene knockout mice | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 98-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 吳華林,高照村,陶祕華,黃麗華,李建國,楊雅倩 | |
| dc.subject.keyword | 穿膜絲胺酸蛋白酶,腫瘤細胞轉移,間隙接合分子,肝細胞生長因子,老鼠模型, | zh_TW |
| dc.subject.keyword | serine protease,metastasis,gap junction,hepatocyte growth factor,mouse model, | en |
| dc.relation.page | 170 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2010-06-25 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| ntu-99-1.pdf 目前未授權公開取用 | 11.72 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。