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研究生(外文):Chin-Liew Chong
論文名稱(外文):Investigation of the role of UK114 in hepatocellular carcinogenesis
指導教授(外文):Chung-Ming Chang
外文關鍵詞:primary hepatocellular carcinomaHCCUK114
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原發性肝細胞癌(primary hepatocellular carcinoma, HCC)是世界上最常見的惡性腫瘤之一。然而,就其病原學上及其分子層面的致病機轉仍不清楚。分析正常肝細胞及肝癌細胞之間基因表現的差異,將有助於鑑定與其致病機轉有關的因子。本論文中,發現UK114,一個主要在肝臟細胞及腎臟細胞中大量表現的蛋白質,其表現量在肝細胞癌組織中有明顯減低的現象,同時其表現量亦隨著癌細胞分化程度變差而下降。此下降情形也同樣出現在HuH7、HepG2及 Hep3B等肝癌細胞株中。在以HepG2或HuH7所建立之UK114的穩定細胞株,似乎具有抑制腫瘤細胞在裸鼠內的腫瘤生成能力。此外,UK114之表現亦會降低細胞株之群落生長能力。但是,大量表現UK114,無法減低HepG2及HuH7細胞之生長速率,及改變HuH7之細胞週期。同時,我們也對UK114的調控加以分析,結果發現UK114的表現似乎不受到其基因體上去氧核糖核酸甲基化(DNA methylation),或是組織蛋白的去乙醯化(histone deacetylation)的影響。因此,UK114在肝癌細胞表現量減少的調控機制目前尚不清楚。總而言之,在近70%的HCC檢體中UK114之表現量均是下降的,而且其表現量與腫瘤之分化程度相關,雖然,UK114不會抑制細胞之生長速率,但會減低肝癌細胞的群落生成及在裸鼠之生長,可見UK114在肝癌之產生及癌化之過程中扮演著重要的角色。
Primary hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. However, the precise molecular mechanisms of HCC pathogenesis are not clear. The comparison of gene expression profiles between primary normal human hepatocytes and primary hepatocellular carcinoma may yield some potential factors that contribute to the pathogenesis of HCC. In this thesis, we found that UK114, a 14.5 kD protein primarily found in liver and kidney, is significantly down-regulated in tumor tissue of HCC as compared to the adjacent normal tissue. Furthermore, the expression level of UK114 is shown to be correlated with the differentiation grade of HCC tissue. Normally, the UK114 expression level in HCC tumor cell lines, such as HepG2, HuH7 and Hep3B, is relatively low. Stable clones of HepG2 and HuH7 that express UK114 seems to have reduced tumorigenicity in vivo and the expression of UK114 is associated with the colony forming activity in vitro. However, the expression of UK114 does not alter the proliferation rate of the cell line in both stable clone and transient transfection model nor it affects the cell cycle patterns of the cell lines. We also investigate mechanism involved in the regulation of UK114 in HCC cell lines. Although our data does not provide a clear mechanism, it does not support the hypothesis that down-regulation of UK114 is mediated by hypermethylation or histone deacethylation. In summary, a large portion of HCC specimens show down-regulation of UK114, and the expression level correlated with the grade of the HCC. Even though over-expression of UK114 has no effect on cell growth, it reduced the in vitro colony forming activity and the in vivo tumorigenecity of the cell lines. We conclude that UK114 might play an important role in hepatocellular carcinogenesis.
Arora, A. S., de Groen, P. C., Croall, D. E., Emori, Y., and Gores, G. J. (1996). Hepatocellular carcinoma cells resist necrosis during anoxia by preventing phospholipase-mediated calpain activation. J Cell Physiol 167, 434-442.
Asagi, K., Oka, T., Arao, K., Suzuki, I., Thakur, M. K., Izumi, K., and Natori, Y. (1998). Purification, characterization and differentiation-dependent expression of a perchloric acid soluble protein from rat kidney. Nephron 79, 80-90.
Bartorelli, A., Berra B., Ronchi S., Biancardi C., Cavalca V., Bailo M., Mor C., Ferrara R., Botta M., Arzani C., and Clemente C.. (1994). Immunocytochemical reactivity of mammalian liver antigen (UK101) in Human Tumors and non Neoplastic tissues. Journal of tumor marker oncology 9, 37-47.
Buendia, M. A. (2000). Genetics of hepatocellular carcinoma. Semin Cancer Biol 10, 185-200.
Bustin, M., Lehn, D. A., and Landsman, D. (1990). Structural features of the HMG chromosomal proteins and their genes. Biochim Biophys Acta 1049, 231-243.
Ceciliani, F., Faotto, L., Negri, A., Colombo, I., Berra, B., Bartorelli, A., and Ronchi, S. (1996). The primary structure of UK114 tumor antigen. FEBS Lett 393, 147-150.
Chen, C. J., Yu, M. W., and Liaw, Y. F. (1997). Epidemiological characteristics and risk factors of hepatocellular carcinoma. J Gastroenterol Hepatol 12, S294-308.
Chomczynski, P., and Sacchi, N. (1987). Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162, 156-159.
Christofori, G., and Semb, H. (1999). The role of the cell-adhesion molecule E-cadherin as a tumour-suppressor gene. Trends Biochem Sci 24, 73-76.
Enos-Berlage, J. L., Langendorf, M. J., and Downs, D. M. (1998). Complex metabolic phenotypes caused by a mutation in yjgF, encoding a member of the highly conserved YER057c/YjgF family of proteins. J Bacteriol 180, 6519-6528.
Goupil-Feuillerat, N., Cocaign-Bousquet, M., Godon, J. J., Ehrlich, S. D., and Renault, P. (1997). Dual role of alpha-acetolactate decarboxylase in Lactococcus lactis subsp. lactis. J Bacteriol 179, 6285-6293.
Graham, F. L., and van der Eb, A. J. (1973). A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology 52, 456-467.
Hsu, I. C., Metcalf, R. A., Sun, T., Welsh, J. A., Wang, N. J., and Harris, C. C. (1991). Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350, 427-428.
Hui, A. M., Makuuchi, M., and Li, X. (1998). Cell cycle regulators and human hepatocarcinogenesis. Hepatogastroenterology 45, 1635-1642.
Ish-Horowicz, D., and Burke, J. F. (1981). Rapid and efficient cosmid cloning. Nucleic Acids Res 9, 2989-2998.
Kaneki, K., Matsumoto, M., Suzuki, K., Akuzawa, M., and Oka, T. (2003). Purification, characterization and developmental expression of pig liver PSP. Comp Biochem Physiol B Biochem Mol Biol 134, 571-578.
Kanouchi, H., Oka, T., Asagi, K., Tachibana, H., and Yamada, K. (2000). Expression and cellular distribution of perchloric acid-soluble protein is dependent on the cell-proliferating states of NRK-52E cells. Cell Mol Life Sci 57, 1103-1108.
Kanouchi, H., Tachibana, H., Oka, T., and Yamada, K. (2001). Recombinant expression of perchloric acid-soluble protein reduces cell proliferation. Cell Mol Life Sci 58, 1340-1343.
Kim, J. M., Yoshikawa, H., and Shirahige, K. (2001). A member of the YER057c/yjgf/Uk114 family links isoleucine biosynthesis and intact mitochondria maintenance in Saccharomyces cerevisiae. Genes Cells 6, 507-517.
Kobryn, C. E., and Fiskum, G. (1992). Differential sensitivity of AS-30D rat hepatoma cells and normal hepatocytes to anoxic cell damage. Am J Physiol 262, C1384-1387.
Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680-685.
Lee, S., Lee, H. J., Kim, J. H., Lee, H. S., Jang, J. J., and Kang, G. H. (2003). Aberrant CpG island hypermethylation along multistep hepatocarcinogenesis. Am J Pathol 163, 1371-1378.
Levy, L., Renard, C. A., Wei, Y., and Buendia, M. A. (2002). Genetic alterations and oncogenic pathways in hepatocellular carcinoma. Ann N Y Acad Sci 963, 21-36.
Lin, Y. W., Sheu, J. C., Huang, G. T., Lee, H. S., Chen, C. H., Wang, J. T., Lee, P. H., and Lu, F. J. (1999). Chromosomal abnormality in hepatocellular carcinoma by comparative genomic hybridisation in Taiwan. Eur J Cancer 35, 652-658.
Mandel, M., and Higa, A. (1970). Calcium-dependent bacteriophage DNA infection. J Mol Biol 53, 159-162.
Matsumura, T., Makino, R., and Mitamura, K. (2001). Frequent down-regulation of E-cadherin by genetic and epigenetic changes in the malignant progression of hepatocellular carcinomas. Clin Cancer Res 7, 594-599.
Melloni, E., Averna, M., Salamino, F., Sparatore, B., Minafra, R., and Pontremoli, S. (2000). Acyl-CoA-binding protein is a potent m-calpain activator. J Biol Chem 275, 82-86.
Melloni, E., Michetti, M., Salamino, F., and Pontremoli, S. (1998). Molecular and functional properties of a calpain activator protein specific for mu-isoforms. J Biol Chem 273, 12827-12831.
Morishita, R., Kawagoshi, A., Sawasaki, T., Madin, K., Ogasawara, T., Oka, T., and Endo, Y. (1999). Ribonuclease activity of rat liver perchloric acid-soluble protein, a potent inhibitor of protein synthesis. J Biol Chem 274, 20688-20692.
Nhieu, J. T., Renard, C. A., Wei, Y., Cherqui, D., Zafrani, E. S., and Buendia, M. A. (1999). Nuclear accumulation of mutated beta-catenin in hepatocellular carcinoma is associated with increased cell proliferation. Am J Pathol 155, 703-710.
Nita, M. E., Alves, V. A., Carrilho, F. J., Ono-Nita, S. K., Mello, E. S., and Gama-Rodrigues, J. J. (2002). Molecular aspects of hepatic carcinogenesis. Rev Inst Med Trop Sao Paulo 44, 39-48.
Nordin, H., Matsumoto, M., Suzuki, K., Kaneki, K., Natori, Y., Kishi, K., and Oka, T. (2001). Purification, characterization and developmental expression of chick (Gallus domesticus) liver PSP protein. Comp Biochem Physiol B Biochem Mol Biol 128, 135-143.
Oka, T., Tsuji, H., Noda, C., Sakai, K., Hong, Y. M., Suzuki, I., Munoz, S., and Natori, Y. (1995). Isolation and characterization of a novel perchloric acid-soluble protein inhibiting cell-free protein synthesis. J Biol Chem 270, 30060-30067.
Oxelmark, E., Marchini, A., Malanchi, I., Magherini, F., Jaquet, L., Hajibagheri, M. A., Blight, K. J., Jauniaux, J. C., and Tommasino, M. (2000). Mmf1p, a novel yeast mitochondrial protein conserved throughout evolution and involved in maintenance of the mitochondrial genome. Mol Cell Biol 20, 7784-7797.
Radloff, R., Bauer, W., and Vinograd, J. (1967). A dye-buoyant-density method for the detection and isolation of closed circular duplex DNA: the closed circular DNA in HeLa cells. Proc Natl Acad Sci U S A 57, 1514-1521.
Raizis, A. M., Schmitt, F., and Jost, J. P. (1995). A bisulfite method of 5-methylcytosine mapping that minimizes template degradation. Anal Biochem 226, 161-166.
Rappu, P., Shin, B. S., Zalkin, H., and Mantsala, P. (1999). A role for a highly conserved protein of unknown function in regulation of Bacillus subtilis purA by the purine repressor. J Bacteriol 181, 3810-3815.
Samuel, S. J., Tzung, S. P., and Cohen, S. A. (1997). Hrp12, a novel heat-responsive, tissue-specific, phosphorylated protein isolated from mouse liver. Hepatology 25, 1213-1222.
Schmiedeknecht, G., Buchler, C., and Schmitz, G. (1997). A bidirectional promoter connects the p14.5 gene to the gene for RNase P and RNase MRP protein subunit hPOP1. Biochem Biophys Res Commun 241, 59-67.
Schmiedeknecht, G., Kerkhoff, C., Orso, E., Stohr, J., Aslanidis, C., Nagy, G. M., Knuechel, R., and Schmitz, G. (1996). Isolation and characterization of a 14.5-kDa trichloroacetic-acid-soluble translational inhibitor protein from human monocytes that is upregulated upon cellular differentiation. Eur J Biochem 242, 339-351.
Schmitz, G., and Downs, D. M. (2004). Reduced transaminase B (IlvE) activity caused by the lack of yjgF is dependent on the status of threonine deaminase (IlvA) in Salmonella enterica serovar Typhimurium. J Bacteriol 186, 803-810.
Shimoyama, Y., and Hirohashi, S. (1991). Cadherin intercellular adhesion molecule in hepatocellular carcinomas: loss of E-cadherin expression in an undifferentiated carcinoma. Cancer Lett 57, 131-135.
Sinha, S., Rappu, P., Lange, S. C., Mantsala, P., Zalkin, H., and Smith, J. L. (1999). Crystal structure of Bacillus subtilis YabJ, a purine regulatory protein and member of the highly conserved YjgF family. Proc Natl Acad Sci U S A 96, 13074-13079.
Tchou, J. C., Lin, X., Freije, D., Isaacs, W. B., Brooks, J. D., Rashid, A., De Marzo, A. M., Kanai, Y., Hirohashi, S., and Nelson, W. G. (2000). GSTP1 CpG island DNA hypermethylation in hepatocellular carcinomas. Int J Oncol 16, 663-676.
Thomas, P. S. (1980). Hybridization of denatured RNA and small DNA fragments transferred to nitrocellulose. Proc Natl Acad Sci U S A 77, 5201-5205.
Wei, Y., Van Nhieu, J. T., Prigent, S., Srivatanakul, P., Tiollais, P., and Buendia, M. A. (2002). Altered expression of E-cadherin in hepatocellular carcinoma: correlations with genetic alterations, beta-catenin expression, and clinical features. Hepatology 36, 692-701.
Yan, J., Yu, Y., Wang, N., Chang, Y., Ying, H., Liu, W., He, J., Li, S., Jiang, W., Li, Y., et al. (2004). LFIRE-1/HFREP-1, a liver-specific gene, is frequently downregulated and has growth suppressor activity in hepatocellular carcinoma. Oncogene 23, 1939-1949.
行政院衛生署 (2003). 中華民國九十一年臺灣地區死因統計結果摘要. 台灣地區死因統計結果摘要.
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