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標題: 過量表現人類血管內皮生長因子A165於基因轉殖小鼠肺部誘導腫瘤之生成
The Pulmonary Tumorigenesis Induced by Human VEGF-A165 Overexpression in the Lung Tissue of Transgenic Mice
作者: 黃彬武
Huang, Pin-Wu
關鍵字: 人類血管內皮生長因子A165
Human VEGF-A165
出版社: 生命科學系所
引用: 行政院衛生署。2005。臺灣主要癌症死亡率趨勢圖。 statistic/data/死因摘要/93年/統計圖/6.男性主要癌症死亡率.xls 陸坤泰、張登斌。1991。本土醫學資料庫之建立及衛生政策上之應用,台灣的肺癌。中華民國台灣醫學會。 taiwan11.htm#top Andersson, O., L. Nordlund-Moller, H. J. Barnes and J. Lund. 1994. Hetero- logous expression of human uteroglobin/polychlorinated biphenyl-binding protein. Determination of ligand binding parameters and mechanism of phospholipase A2 inhibition in vitro. J. Biol. Chem. 269: 19081-19087. Avanzo, J. L., M. Mesnil, F. J. Hernandez-Blazquez, I. I. Mackowiak, C. M. Mori, T. C. da Sliva, S. C. Oloris, A. P. Garate, S. M. Massironi, H. Yamasaki and M. L. Dagli. 2004. Increased susceptibility to urethane-induced lung tumors in mice with decreased expression of connexin43. Carcinogenesis 25:1973- 19782. Barleon, B., S. Sozzani, D. Zhou., H. A. Weich, A. Mantovani and D. Marme. 1996. Migration of human monocytes in response to vascular endothelial growth factor is mediated via the VEGF receptor flt-1. Blood 87: 3336-3343. Barnes, H. J., L. Nordlund-Moller, M. Nord, O. Andersson, J. A. Gustafsson, J. Lund and M. Gillner. 1996. Structural basis for calcium binding by uteroglobins. J. Mol. Biol. 256: 392-404. Beer, D. G. and A. M. Malkinson. 1985. Genetic influence on type 2 or Clara cell origin of pulmonary adenomas in urethan-treated mice. J. Natl. Cancer Inst. 75: 963-969. Bellomo, D., J. P. Headrick, G. U. Silins, C. A. Paterson, P. S. Thomas, M. Gartside, A. Mould, M. M. Cahill, I. D. Tonks, S. M. Grimmond, S. Townson, C. Wells, M. Little, M. C. Cummings, N. K. Hayward and G. F. Kay. 2000. Mice lacking the vascular endothelial growth factor-B gene (VEGF-B) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ. Res. 86: E29-E35. Bernard, A., X. Dumont, H. Roels, R. Lauwerys, I. Dierynck, M. De Ley, V. Stroobant, E. de Hoffmann.1993. The molecular mass and concentrations of protein 1 or Clara cell protein in biological fluids: a reappraisal. Clin. Chim. Acta. 223: 189-191. Bhardwaj, S., H. Roy, T. Heikura and S. Ylä-Herttuala. 2006. VEGF-A, VEGF-D and VEGF-DΔNΔC induced intimal hyperplasia in carotid arteries. Eur. J. Clin. Invest. 35: 669-676. Bilello, K. S., S. Murin and R. A. Matthay. 2002. Epidemiology, etiology, and prevention of lung cancer. Clin. Chest Med. 23: 1-25. Bischoff, J. 1997. Cell adhesion and angiogenesis. J. Clin. Invest. 100: 37-39. Blasi, F. 1997. uPA, uPAR, PAI-1, key intersection of proteolytic, adhesive and chemotactic highways? Immunol. Today 18: 415-417. Born, S. L., A. S. Fix, D. Caudill and L. D. Lehman-McKeeman. 1998. Selective Clara cell injury in mouse lung following acute administration of coumarin. Toxicol. Appl. Pharmacol. 151: 45-56. Brambilla, E. 2005. Large cell carcinomas. Breath 1: 315-319. Brambilla, E., W. D. Travis, T. V. Coblly, B. Colby and Y. Shimosato. 2001. The new world health organization classification of lung tumours. Eur. Respir. J. 18: 1059-1068. Bremnes, R. M., C. Camps and R. Sirera. 2006. Angiogenesis in non-small cell lung cancer: the prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung cancer. 51: 143-158. Butt A. J., C. M. McNeil, E. A. Musgrove and R. L. Sutherland. 2005. Down- stream targets of growth factor and oestrogen signalling and endocrine resistance: The potential roles of c-Myc, cyclin D1 and cyclin E. Endocr. Relat. Cancer. 1: 47-59. Cameliet, P. 2003. Angiogenesis in health and disease. Nat. Med. 9: 653-660. Chang, F., L. S. Steelman, J. G. Shelton, J. T. Lee, P. M. Navolanic, W. L. Blalock, R. Franklin, J. A. McCubery. 2003.Regulation of cell cycle progression and apoptosis by the Ras/Raf/MEK/ERK pathway (Review). Int. J. Oncol. 22: 469-480. Clark, D. E., S. K. Smith, Y. He, K. A. Dat, D. R. Licence, A. N. Corps, R. La- mmoglia and D. S. Charnock-Jones. 1998. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol. Reprod. 59: 1540-1548. Clark, D. E., S. K. Smitha, Y. Hea, K. A. Day, D. R. Licence, A. N. Corps, R. Lammoglia and D. S. Charnock-Jones. 1998. A vascular endothelial growth factor antagonist is produced by the human placenta and released into the maternal circulation. Biol. Reprod. 59: 1540-1548. Connolly D. T., J. V. Olander, D. Heuvelman, R. Nelson, R. Monsell, N. Siegel, B. L. Haymore, R. Leimgruber and J. Feder. 1989. Human vascular perme- ability factor:Isolation from U937 cells. J. Biol. Chem. 254: 20017-20024. Conte, M. S., D. C. Altieri. 2006. Survivin regulation of vascular injury. Trends. Cardiovasc. Med. 16: 114-117. Cross, M. J., J. Dixelius, T. Matsumoto and L. Claesson-Welsh. 2003. VEGF-receptor signal transduction. Trends Biochem. Sci. 28: 488-494. De Falco, S., B. Gigante and M. G. Persico. 2002. Structure and function of placental growth factor. Trends Cardiovasc. Med. 12: 241-246. Donnelly, P. J. and T. E. Massey. 1999. Ki-ras activation in lung cells isolated from AC3F1 (A/J x C3H/HeJ) mice after treatment with aflatoxin B1. Mol. Carcinog. 26: 62-67. Dosaka, A. H., E. Miyoshi, O. Suzuki, T. Itoh, H. Katoh, N. Taniguchi. 2004. Expression of N-acetylglucosaminyltransferase v is associated with prognosis and histology in non-small cell lung cancers. Clin. Cancer Res. 10:1773-1779. Dumont, D. J., L. Jussila, J. Taipale, A. Lymboussaki, T. Mustonen, K. Pajusola, M. Breitman and K. Alitalo. 1998. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282: 946-949. Dvorak, H. F. 2003. How tumors make bad blood vessels and stroma. Am. J. Pathol. 162: 1747-1757. Dvorak, H. F. 2005. Angiogenesis: update 2005. J. Thromb. Haemost. 3: 1835- 1842. Ferrara, N. 2002. VEGF and the request for tumour angiogenesis factors. Nat. Rev. Cancer 2: 795-803. Ferrara, N., H. P. Gerber and J. LeCouter. 2003. The biology of VEGF and its receptors. Nat. Med. 6: 669-676. Ferrara, N. and T. Davis-Smyth. 1997. The biology of vascular endothelial growth factor. Endocr. Rev. 18: 4-25. Fong, G. H., L. Zhang, D. M. Bryce and J. Peng. 1999. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development 126: 3015-3025. Fong, G. H., J.Rossant, M.Gertsenstein and M. L.Breitman. 2002. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothe- lium. Nature 376: 66-70. Forsythe, J. A., B. H. Jiang, N. V. Iyer, F. Agani, S. W. Leung, R. D. Koos and G. L. Semenza. 2002. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16: 4604-4613. Foster, M. R., J. E. Johnson, S. J. Olson and D. C. Allred. 2001. Immuno- histochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesotheliomas and primary pulmonary adenocarcinomas. Arch. Pathol. Lab. Med. 125: 1316-1320. Franklin, W. A. 2000. Diagnosis of lung cancer: Pathology of invasive and pre- invasive neoplasia. Chest 117: 80-89. Fulton, D., J. P. Gratton, T. J. McCabe, J. Fontana, Y. Fujio, K. Walsh, T. F. Franke, A. Papapetropoulos and W. C. Sessa. 1999. Regulation of endothe- lium-derived nitric oxide production by the protein kinase Akt. Nature 399: 597-601. Gasparini, G. 1999. The rationale and future potential of angiogenesis inhibitor in neoplasia. Drugs 58: 17-38. Gerber, H. P., V. Dixit and N. Ferrara. 1998. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. J. Biol. Chem. 273: 13313-13316. Gerber, H.P., A. McMurtrey, J. Kowalski, M. Yan, B. A. Keyt, V. Dixit and N. Ferrara. 1998. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway: Requirement for Flk-1/KDR activation. J. Biol. Chem. 273: 30336-30343. Gerber, H. P., A. McMurtrey, J. Kowalski, M. Yan, B. A. Keyt, V. Dixit and N. Ferrara. 1998. Vascular endothelial growth factor regulated endothelial cell survival through the phosphatidylinositol 3''-kinase/Akt signal transduction pathway. J. Biol. Chem. 273: 30336-30343. Glading, A., D. A. Lauffenburger and A. Wells. 2002. Cutting to the chase: Calpain proteases in cell motility. Trends. Cell. Biol. 12: 46-54. Gordon, J. W., G. A. Scangos, D. J. Plotkin, J. A. Barbosa and F. H. Ruddle. 1980. Genetic transformation of mouse embryos by microinjection of purified DNA. Proc. Natl. Acad. Sci. USA 77: 7380- 7384. Gossler, A., T. Doetschman, R. Korn, E. Serfling and R. Kemler. 1986. Trans- genesis by means of blastocyst-derived embryonic stem cell lines. Proc. Natl. Acad. Sci. USA 83: 9065-9069. Graves, R. J., C. Coutts and T. Green 1995. Methylene chloride- induced DNA damage: An interspecies comparison. Carcinogenesis. 16 : 1919-1926. Hamada, K., Y. Oike, N. Takakura, Y. Ito, L. Jussila, D. J. Dumont, K. Alitalo and T. Suda. 2000. VEGF-C signaling pathways through VEGFR-2 and VEGFR-3 in vasculoangiogenesis and hematopoiesis. Blood 96: 3793-800. Hart, I. R. and A. Saini. 1992. Biology of tumor metastasis. Lancet. 339: 1453- 1457. Hay, J. G., C. Danel, C. S. Chu and R. G. Crystal. 1995. Human CC10 gene expression in airway epithelium and subchromosomal locus suggest linkage to airway disease. Am. J. Physiol. 268: 565-575. He, Y., K. Kozaki, T. Karpanen, K. Koshikawa, S. Yla-Herttuala, T. Takahashi and K. Alitalo. 2002. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J. Natl. Cancer Inst. 94: 819-825. Hecht, S. S. 1998. Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem. Res. Toxicol. 11: 559-603. Hermans, C. and A. Bernard. 1999. Lung epithelium-specific proteins: character- ristics and potential applications as markers. Am. J. Respir. Crit. Care Med. 159: 646-678. Hermans, C., B. Knoops, M. Wiedig, K. Arsalane, G. Toubeau, P. Falmagne and A. Bernard. 1999. Clara cell protein as a marker of Clara cell damage and bronchoalveolar blood barrier permeability. Eur. Respir. J. 13: 1014-1021. Hicks, S. M., J. D. Vassallo, M. Z. Dieter, C. L. Lewis, L. O. Whiteley, A. S. Fix and L. D. Lehman-McKeeman. 2003. Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis. Toxicology 187: 217-228. Hiratsuka, S., O. Minowa, J. Kuno, T. Noda and M. Shibuya. 1998. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angio- genesis in mice. Proc. Natl. Acad. Sci. USA 95: 9349-9354. Ho, Y. S., C. H. Chen, Y. J. Wang, R. G. Pestell, C. Albanese, R. J. Chen, M. C. Chang, J. H. Jeng, S. Y. Lin, Y. C. Liang, H. Tseng, W. S. Lee, J. K. Lin, J. S. Chu, L. C. Chen, C. H. Lee, W. L. Tso, Y. C. Lai and C. H. Wu. 2005. Tobacco-specific carcinogen 4-(methylnitrosamino) -1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFkappaB activation and cyclin D1 up-regulation. Toxicol. Appl. Pharmacol. 205:133-148. Hoffmann, D., I. Hoffmann and K. El-Bayoumy. 2001. The less harmful cigarette: A controversial issue-a tribute to Ernst L. Wynder. Chem. Res. Toxicol. 14: 767-790. Hong, K. U., S. D. Reynolds, A. Giangreco, C. M. Hurley and B. R. Stripp. 2001. Clara cell secretory protein-expressing cells of the airway neuroepithelial body microenvironment include a label-retaining subset and are critical for epithelial renewal after progenitor cell depletion. Am. J. Respir. Cell. Mol. Biol. 24: 671-681. Houck, K. A., N. Ferrara, J. Winer, G. Cachianes, B. Li and D. W. Leung. 1991. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol. Endorcrinol. 5: 1806-1814. Jackson, P.J., R. Turner., J. N. Keen., R. A. Brooksbank and E. H. Cooper. 1988. Purification and partial amino acid sequence of human urine protein 1: Evidence for homology with rabbit uteroglobin. J. Chromatogr. 1452: 359-367. Jagannath, C., H. Hoffmann, E. Sepulveda, J. K. Actor, R. A. Wetsel and R. L. Hunter JR. 2000. Hypersusceptibility of A/J mice to tuberculosis is in part due to a deficiency of the fifth complement component (C5) Scand J. Immunol. 52: 369-379. Jalas, T. R., X. Ding and S. E. Murphy. 2003. Comparative metabolism of NNK and NNAL by rat cytochrome P450 2A3 and human cytochrome 2A13. Drug Metab. Dispos. 31: 1199-1202. Janeisch, R. 1976. Germ line integration and Mendelian transmission of the exogenous Moloney leukemia virus. Proc. Natl. Acad. Sci. USA 73: 1260- 1264. Jiang, Y., H. I. Saavedra, M. P. Holloway, G. Leone and R. A. Altura. 2004. Aberrant regulation of survivin by the RB/E2F family of proteins. J. Biol. Chem. 279: 40511-40520. Johnston, C. J., G. W. Mango, J. N. Finkelstein and B. R. Stripp. 1997. Altered pulmonary response to hyperoxia in Clara cell secretory protein deficient mice. Am. J. Respir. Cell. Mol. Biol. 17: 147-155. Johnston, C. J., B. R. Stripp, B. Piedbeouf, T. W. Wright, G. W. Mango, C. K. Reed and J. N. Finkelstein. 1988. Inflammatory and epithelial responses in mouse strains that differ in sensitivity to hyperoxic injury. Exp. Lung Res. 24: 189-202. Joukov, V., T. Sorsa, V. Kumar, M. Jeltsch, L. Claesson-Welsh, Y. Cao, O. Saksela, N. Kalkkinen and K. Alitalo. 1997. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO. J. 16: 3898-3911. Katoch, O., H. Tauchi, K. Kawaishi, A. Kimura and Y. Satow. 1995. Expression of the vascular endothelial growth factor (VEGF) receptor gene, KDR, in hematopoietic cells and inhibitory effect of VEGF on apoptotic cell death caused by ionizing radiation. Cancer Res. 55: 5687-5692. Kaynak, K., M. Kara, B. Oz, B. Akgoz, M. Sar, and A. Raz. 2005. Autocrine motility factor receptor expression implies an unfavourable prognosis in resected stage I pulmonary adenocarcinomas. Acta. Chir. Belg. 105: 378-382. Keyt, B. A., L. T. Berleau, H. V. Nguyen, H. Chen, H. Heinsohn, R. Vandlen and N. Ferrara. 1996. The carboxyl-terminal domain of vascular endothelial growth factor is critical for its mitogenic potency. J. Biol. Chem. 271: 7788-7795. Khoor, A., M. E. Gray, G. Singh and M. T. Stahlman.. 1996. Ontogeny of Clara cell-specific protein and its mRNA: their association with neuroepithelial bodies in human fetal lung and in bronchopulmonary dysplasia. J. Histochem. Cytochem. 44: 1429-1438. La Vecchia, C., S. Franceschi and F. Levi. 2003. Epidemiological research on cancer with a focus on Europe. Eur. J. Cancer Prev. 12: 5-14. Laing, L. A., C. Hermans, A. Bernard, P. R. Burton, J. Goldblatt, and P. N. Le Souef. 2000. Association between plasma CC16 levels, the A38G polymorphism, and asthma. Am. J. Respir. Crit. Care. Med. 161: 124-127. Lavitrano, M., A. Camaioni, V. M. Fazio, S. Dolci, M. G. Farace and C. Spara- dafor. 1989. Sperm cells as vectors for introducing foreign DNA into eggs: Genetic transformation of mice. Cell 57: 717-723. Leyton, L., M. J. Manyak, A. B. Mukherjee, L. Miele, G. Mantile and S. R. Patierno. 1994. Recombinant human uteroglobin inhibits the in vitro invasiveness of human metastatic prostate tumor cells and the release of arachidonic acid stimulated by fibroblast-conditioned medium. Cancer Res. 54: 3696-3699. Liotta, L. A. 2001. An attractive force in metastasis. Nature 410: 24-25. Malkinson, A. M. 1998. Molecular comparison of human and mouse pulmonary adenocarcinomas. Exp. Lung Res. 24: 541-555. Martinez-Moreno, P., S. Nieto-Ceron, J. Torres-Lanzas, F. Ruiz-Espejo, I. Tovar-Zapata, P. Martinez-Hernandez, J. N. Rodriguez-Lopez, C. J. Vidal and J. Cabezas-Herrera. 2005. Cholinesterase activity of human lung tumours varies according to their histological classification. Cancinogensis 27: 429- 436. Matta, J., M. Lehto, S. Tillander, R. Haapakoski, M. L. Majuri, H. Wolff, S. Rautio, I. Welling, P. K. Husgafvel, K. Savolainen and H. Alenius. 2006. Mechanisms of particle-induced pulmonary inflammation in a mouse model: exposure to wood dust. Toxicol. Sci. Epub ahead of print. McKeever, D. J., D. M. Jenkinson, G. Hutchison and H. W. Reid. 1988. Studies of the pathogenesis of orf virus infection in sheep. J. Comp. Pathol. 99: 317-328. Miele, L., L. Cordella-Miele and A. B. Mukherjee. 1987. Uteroglobin: structure, molecular biology, and new perspectives on its function as a phospholipase A2 inhibitor. Endocr. Rev. 8: 474-490. Mignatti, P. and D. B. Rifkin. 1996. Plasminogen activators and matrix meta- lloproteinase in angiogenesis. Enzyme Protein 49: 117-137. Minna, J. D., J. A. Roth and A. F. Gazdar. 2002. Focus on lung cancer. Cancer Cell 1: 49-52. Murphy, G., H. Stanton, S. Cowell, G. Butler, V. Knauper, S. Atkinson and J. Gavrilovic. 1999. Mechanisms for pro matrix metalloproteinase activation. Acta Pathol. Microbiol. Immun. Scand. 107: 38-44. Nash, A. D., M. Baca, C. Wright and P. D. Scotney. 2005. The biology of vas- cular endothelial growth factor-B (VEGF-B). Pulm. Pharmacol. Ther. 19: 61-69. Ng, Y. S., R. Rohan, M. E. Sunday, D. E. Demello and P. A. D''Amore. 2001. Differential expression of VEGF isoforms in mouse during development and in the adult. Dev. Dyn. 220: 112-121. Nonaka, D., R. Birbe and J. Rosai. 2005. So-called inflammatory myofibroblastic tumour: A proliferative lesion of fibroblastic reticulum cells? Histopathology 46: 604-613. Oh, S. J., M. M. Jeltsch, R. Birkenhäger, J. E. G. McCarthy, H. A. Weich, B. Christ, K. Alitalo and J. Wilting. 1997. VEGF and VEGF-C: Specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev. Biol. 188: 96-109. Qi, J. H. and L. Claesson-Welsh. 2001. VEGF-induced activation of phosphor- inositide 3-kinase is dependent on focal adhesion kinase. Exp. Cell Res. 263: 173-182. Olofsson, B., K. Pajusola, A. Kaipainen, G. von Euler, V. Joukov, O. Saksela, A. Orpana, R. F. Pettersson, K. Alitalo and U. Eriksson. 1996. Vascular endothe- lial growth factor B, a novel growth factor for endothelial cells. Proc. Natl. Acad. Sci. USA 93: 2576-2581. Pajusola, K., O. Aprelikova, G. Pelicci, H. Weich, L. Claesson-Welsh and K. Alitalo. 1994. Signalling properties of FLT4, a proteolytically processed recaptor tyrosine kinase related to two VEGF receptors. Oncogene 9: 3545- 3555. Peto, R., S. Darby, H. Deo, P. Silcocks, E. Whitley and R. Doll. 2000. Smoking, smoking cessation, and lung cancer in the UK since 1950: Combination of national statistics with two case-control studies. Brit. Med. J. 321: 323-329. Qi, J. H. and L. Claesson-Welsh. 2001. VEGF-induced activation of phosphor- inositide 3-kinase is dependent on focal adhesion kinase. Exp. Cell. Res. 263: 173-182. Rafii, S., D. Lyden, R. Benezra, K. Hattori and B. Heissig. 2002. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat. Rev. Cancer 2: 826-835. Rosell, R., M. Monz, A. Pifarre, A. Ariza, J. J. Sanchez, I. Moreno, J. Maurel, M. P. Lopez, A. Abad and J. M. de Anta. 1996. Molecular staging of non-small cell lung cancer according to K-ras genotypes. Clin. Cancer Res. 2: 1083-1086. Rousseau, S., F. Houle, J. Landry and J. Huot. 1997. P38 MAP kinase activation by vascular endothelial growth factor mediates actin reorganization and cell migration in human endothelial cells. Oncogene 15: 2169-2177. Ruoslahti, E. 1996. How cancer spreads. Sci. Am. 275: 72-77. Ryan, R. M., M. M. Mineo-Kuhn, C. M. Kramer and J. N. Finkelstein. 1994. Growth factors alter neonatal type II alveolar epithelial cell proliferation. Am. J. Physiol. 266: 17-22. Sah, N. K., Z. Khan, G. J. Khan and P. S. Bisen. 2006. Structural, functional and therapeutic biology of survivin. Cancer Lett. Epub ahead of print. Santella. R. M., R. A. Grinberg-Funes, T. L. Young, C. Dickey, V. N. Singh, L. W. Wang and F. P. Perera. 1992. Cigarette smoking related polycyclic aroma- tic hydrocarbon-DNA adducts in peripheral monon- uclear cells. Carcino- genesis 13: 2041-2045. Schuller, H. M. and M. Cekanova. 2005. NNK-induced hamster lung adeno- carcinomas over-express beta2-adrenergic and EGFR signaling pathways. Lung Cancer 49: 35-45. Senger, D. R., S. J Galli, A. M. Dvorak, C. A. Perruzzi, V. S. Harvey and H. F. Dvorak. 1983. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219: 983-985. Shalaby, F., J. Rossant, T. P. Yamaguchi, M. Gertsenstein, X. F. Wu, M. L. Breitman and A. C. Schuh. 1995. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376: 62-66. Shibuya M. 2003. Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E. Cancer Sci. 94: 751-756. Shima, D. T., M. Kuroki ,U. Deutsch ,Y. S. Ng , A. P. Adamis and P. A. D''Amore. 1996. The mouse gene for vascular endothelial growth factor. J. Biol. Chem. 271: 3871-3883. Simonato, L., A. Agudo, W. Ahrens, E. Benhamou, S. Benhamou, P. Boffetta, P. Brennan, S. C. Darby, F. Forastiere, C. Fortes, V. Gaborieau, M. Gerken, C. A. Gonzales, K. H. Jöckel, M. Kreuzer, F. Merletti, F. Nyberg, G. Pershagen, H. Pohlabeln, F. Rösch, E. Whitley, H. E. Wichmann, and P. Zambon. 2001. Lung cancer and cigarette smoking in Europe: An update of risk estimates and an assessment of inter-country heterogeneity. Int. J. Cancer. 91: 876-887. Singh, G., J. Singh, S. L. Katyal, W. E. Brown, J. A. Kramps, I L. Paradis, J. H. Dauber, T. A. Macpherson and N. Squeglia. 1988. Identification, cellular localization, isolation, and characterization of human Clara cell-specific 10 KD protein. J. Histochem. Cytochem. 36: 73-80. Singh, G., S. L. Katyal, W. E. Brown, A. L. Kennedy, U. Singh and M. L. Wong-Chong. 1990. Clara cell 10 kDa protein (CC10): Comparison of structure and function to uteroglobin. Biochim. Biophys. Acta. 1039: 348-355. Soker, S., S. Takashima, H. Q. Miao, G. Neufeld and M. Klagsbrun. 1998. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform- specific receptor for vascular endothelial growth factor. Cell. 92: 735-745. Stice, S. L., N. S. Strelechenko, C. L. Keefer and L. Matthews.1996. Pluripotent bovine embryonic cell lines direct embryonic development following nuclear transfer. Biol. Reprod. 54: 100-110. Sun, C. X., H. Zhong, A. Mohsenin, E. Morschl, J. L. Chunn, J. G. Molina, L. Belardinelli, D. Zeng, and M. R. Blackburn. 2006. Role of A2B adenosine receptor signaling in adenosine-dependent pulmonary inflammation and injury. J. Clin. Invest. Epub ahead of print. Swidizinska E., M. Ossolinska, W. Naumnik, T. Izycki and E. Chyczewska. 2004. Circulating VEGF and its soluble receptor sVEGFR-1 in patients with lung cancer. Pneumonol. Alergol. Pol. 72: 389-394. Takahashi, T., H. Ueno and M. Shibuya. 1999. VEGF activates protein kinase C-dependent, but Ras-independent Raf-MEK-MAP kinase pathway for DNA synthesis in primary endothelial cells. Oncogene 18: 2221-2230. Takeuchi, H., K. Saoo, Y. Matsuda, M. Yokohira, K. Yamakawa, Y. Zeng, M. Miyazaki, M. Fujieda, T. Kamataki and K. Imaida. 2006. Dose dependent inhibitory effects of dietary 8-methoxypsoralen on NNK-induced lung tumorigenesis in female A/J mice. Cancer Lett. 234: 232-238. Tammela, T., B. Enholm, K. Alitalo and K. Pavvonen. 2004. The biology of vascular endothelial growth factors. J. Cardio. Res. 65: 550-563. Tran J., J. Rak, C. Sheehan, S. D. Saibil, E. LaCasse, R. G. Korneluk and R. S. Kerbel. 1999. Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem. Biophys. Res. Commun. 264: 781-788. Vincenti, V., C. Cassano, M. Rocchi and M. G. Persico. 1996. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation 93: 1493-1495. Weeraratna, A. T., J. A. Cajigas, A. Schwartz, E. G. Enquist, M. J. Manyak and S. R. Patierno. 1997. Loss of uteroglobin expression in prostate cancer: relation- ship to advancing grade. Clin. Cancer Res. 3: 2295-2300. Wheatly, S. P., I. A. McNeish. 2005. Survivin: a protein with dual roles in mitosis and apoptosis. Int. Rev. Cytol. 247: 35-88. Wheeler, M. B. 1994. Development and validation of swine embryonic stem cells: a review. Reprod. Fertil. Dev. 6: 563-568. Wong, H. L., X. Zhang, Q. Y. Zhang, J. Gu, X. Ding, S. S. Hecht, and S. E. Murphy. 2005. Metabolic activation of the tobacco carcinogen 4-(methylnitro- samino)-(3-pyridyl)-1-butanone by cytochrome P450 2A13 in human fetal nasal microsomes. Chem. Res. Toxicol. 18: 913-918. Xu, L. and X. Deng. 2004. Tobacco-specific nitrosamine 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanone induces phosphorylation of mu- and m-calpain in association with increased secretion, cell migration, and invasion. J. Biol. Chem. 279: 53683-53690. Zachary I. 2003. VEGF signalling: Integration and multi-tasking in endothelial cell biology. Biochem. Soc. Trans. 31: 1171-1177. Zachary, I. and G. Gliki. 2000. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc. Res. 49: 568-581.
摘要: 摘要 血管內皮成長因子(vascular endothelial growth factor, VEGF)家族可分為PIGF、VEGF-A、B、C、D、E共六個成員,其中VEGF-A可依mRNA不同剪接(alternative splicing)而分為各種異構型(isoforms),其中較常見的有VEGF-A206、VEGF-A189、VEGF-A165與VEGF-A121等四種異構型,而VEGF-A165 為主要執行功能之異構型。一般而言,VEGF-A具有促進血管增生(angiogenesis),增加血管壁通透性,促進細胞存活以及促進細胞遷移(cell migration)之功能,並於許多試驗中得知於腫瘤生長過程中VEGF-A表現量會聚集增加,具有增加腫瘤生長與促進腫瘤轉移(metastasis)之功能。Clara cell secretory protein (CCSP)係由一種稱為clara cell之非纖維性釋泌細胞所分泌的蛋白,Clara cell主要分佈於肺部支氣管及支氣管末梢之表皮部分,係為一種多功能性細胞,可以分化為許多肺部組織細胞以達到修補之功能;CCSP蛋白亦稱之為CC10、CC16或urine protein 1,係一種保護性蛋白,具有抑制免疫反應,降低發炎反應之效能。基於以上因素本試驗採用CCSP之啟動子銜接人類血管內皮成長因子A165[ccsp-Vegf-A165-sv40 poly(A)]之建構基因進行顯微原核注射,以建立一套於鼠肺支氣管上皮專一性表現之基因轉殖小鼠動物模式。於顯微原核注射後共產製出3隻基因轉殖小鼠,並以南方墨點法與聚合酶鏈鎖反應分析確認該Vegf-A165轉殖基因得以傳承於小鼠後代,進一步以反轉錄聚合酶鏈鎖反應與西方墨點法發現該Vegf-A165轉殖基因於小鼠肺部具有專一性之表現,並於病理組織切片分析結果發現於32隻Vegf-A165基因轉殖小鼠中,呈現支氣管表皮扁平化(96%)、支氣管表面細胞異常增生(93%)、發炎反應(43%)、纖維化(40%)、腺癌(18%)、囊胞(18%)等異常現象產生。進一步試驗結果顯示VEGF-A165具有促進ERK2磷酸化、survivin mRNA、cyclin D1 mRNA表現量增加,而該三種蛋白係為主要與細胞增生相關之蛋白,因此推測VEGF-A165係藉由活化ERK1/2之MAPK訊息傳導路徑依序增加cyclin D1 mRNA與survivin mRNA表現,以達到促使支氣管上皮細胞新生之目的。
Abstract The vascular endothelial growth factor (VEGF) family members consist of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E and placental growth factor (PlGF). VEGF-A has at least nine subtypes due to the alternative splicing of a single gene and the the VEGF-A165 isoform plays a central role in vascular development. VEGF-A exhibits two major biological activities: One is the capacity to stimulate vascular endothelial cell proliferation, and the other is the ability to increase vascular permeability. VEGF-A also promotes the survival and migration of endothelial cells. VEGF-A and its receptor are involved in carcinogenesis, invasion and distant metastasis as well as tumor angiogenesis. Clara cell secretory protein (CCSP) is a protein that is secreted by nonciliated, nonmucous clara cells in the pulmonary airway. CCSP plays a protective role against pulmonary inflammatory response. CCSP is a potent natural immunosuppressor and anti-inflammatory agent. In this study, ccsp-Vegf-A165- sv40 poly(A) was constructed for the production of lung-specific overexpressing VEGF-A165 transgenic mice by microinjection. The results of PCR and Southern blot showed that there were three transgenic mice producted by that microinjection. Further, the results of Southern blot indicated there were the same patterns of the foreign gene within the genome of the transgenic founder mice and their offsprings. The data showed that Vegf-A165 mRNA can be expressed specifically in the lung tissue of the transgenic mice. And the results of Western blot also showed that the VEGF-A165 can be expressed in the lung tissue of the transgenic mice. In the histopathologic slides of the lung tissue in the transgenic mice, it seemed that VEGF-A165 overexpression can induce bronchial epithelium flattened(96%), abnormal proliferation of cells on bronchial epithelium(93%), inflammation(43%), fibrosis(40%), adenoma(18%) and cyst(18%) in the total examination of 32 transgenic mice. Further, the results showed that VEGF-A165 can promote phosphorylation of ERK2, increase the expression of cyclin D1 and survivin mRNA. All of the above suggest that VEGF-A165 induced the proliferation of cells on the bronchial epithelium of the transgenic mice through ERK1/2 MAPK pathway.
其他識別: U0005-2508200610422500
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