Studies on the function of HCC- associated genes, Fetuin-A and Fetuin-B
Autor: | Bo-Wen Zhan, 詹博文 |
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Rok vydání: | 2006 |
Druh dokumentu: | 學位論文 ; thesis |
Popis: | 94 Hepatocellular carcinoma (HCC) is one of the most frequent neoplasms worldwide. Therefore, finding new markers or associated genes is very important in its diagnosis and treatment. In previous study, using full-length cDNA library of HCC constructed by Dr. C.C. Tsai in our laboratory, we found several cystatin-derived genes, such as histidine-rich glycoprotein (HRGP), fetuin-A (a2-HS-glycoprotein), Fetuin-B, and kininogen, showed remarkable down-regulation in tumor tissues compared to their adjacent normal tissues. Cystatins are considered physiological inhibitors of lysosomal cysteine proteases. The cystatin “superfamily” encompasses proteins that contain multiple cystatin-like sequences. Fetuins are members of cystatin superfamily and are negative acute phase proteins in that their serum concentration drops after trauma, infection, and inflammation. Fetuins have been proposed to have several cellular functions including inhibition of tyrosine kinase activity of the insulin receptor, opsonization of macrophage-deactivating molecules, regulation of osteogenesis, inhibition of apatite formation and undesirable calcification. In the present study, we demonstrated that the mRNA and protein levels of fetuin-A and -B were remarkable down-regulated in HCC tissue pairs by quantitative real-time PCR and immunohistochemical staining. Over-expression of fetuin-A in SK-Hep-1 cell line caused down-regulation of MMP-2 at mRNA level without affecting cell proliferation. However, when we further analyze the fetuin protein patterns presented in HCC tissue pairs by Western blotting analysis, we surprisingly found that the level of fetuin protein in HCC tissues was higher than that of adjacent normal tissues. This phenomenon could be caused by more blood vessels in HCC tissues than normal tissues. By treating HCC cells with fetuin-A protein, it caused the increase of cell proliferation, and down-regulation of E-cadherin, whereas it activated PI3K signal pathway to enhance the cell motility of highly invasive HCC cells. It suggested that the late-stage HCC tumor tissues possessing more receptors of fetuin-A and higher amount of fetuin-A from blood vessels, and thus they are more sensitive to fetuin-A stimulation even if the fetuin-A synthesis was down-regulated. |
Databáze: | Networked Digital Library of Theses & Dissertations |
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