肝癌在台灣是一個普遍的癌症， 而SOD1 (copper/zinc superoixde
dismutase or superixde dismutase 1) 廣泛存在並占所有SODs的90%，其生
理機轉是將O2
–轉變成H2O2。 在人類肝癌樣本及細胞中已經證實SOD1
的表現減弱。 但是， SOD1減弱與肝癌形成的關聯目前仍然不清楚。 在
本論文中， 首先證明在人類惡性肝癌SK-Hep-1細胞SOD1的含量較良性
肝癌細胞少。此外，在惡性Novikoff 肝癌N1-S1細胞之SOD1含量也較良
性肝細胞或組織有減少的情形。 利用腺病毒載體傳送SOD1基因增加
SOD1蛋白表現量30-40%，可減少O2
–含量及增加H2O2產生。 SOD1基因
傳送顯著抑制SK-Hep1細胞的增殖，轉移和菌落生長，但不影響
metalloproteinase-2 (MMP-2)和MMP-9的分泌。 Flow cytometry分析指出
SOD1基因傳送抑制誘導之細胞週期停止，是經由減少cdk1、 cdk4及
cyclin A、cyclin D1的表現，及增加p21Cip1和 p27kip1的生成有關。 SOD1
基因傳送可減少NF-κB的活性,進而減弱SK-Hep-1細胞的增殖及轉移。
結論, 本論文證明增加SOD1的表現可減弱SK-Hep-1肝癌細胞之致癌
性。

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers in
Taiwan. Copper-zinc superoxide dismutase (SOD1) is widely distributed and
comprises 90% of the total superoxide dismutase (SOD), which catalyzes the
conversion of superoxide to hydrogen peroxide. Reduced expression of
antioxidant enzymes, particularly SOD1, has been identified in human
hepatoma specimens and cell lines. However, it remains unclear how SOD1
expression affected the tumorigenic processes of hepatoma cells. Expression
analysis of an array of human HCC cell lines revealed that SOD1 protein
levels were down regulated in poorly differentiated SK-Hep-1 cells.
Adenovirus-mediated SOD1 expression increased the SOD1 protein level by
30-40% of control. In addition, SOD1 gene transfer decreased the cellular
O2
– level yet increased the H2O2 production. SOD1 overexpression
significantly reduced the proliferation, motility, and anchorage-independent
growth of SK-Hep-1 cells, but had no effect on the secretion of matrix
metalloproteinase-2 (MMP-2) and MMP-9. SOD1 restoration inhibited the
proliferation of SK-Hep-1 cells through induction of cell cycle arrest, which
was associated with decreased expression of cyclin A, cyclin D1, cdk1, cdk4
and upregulation of p21Cip1 and p27kip1. Besides, SOD1 overexpression also
inhibited the nuclear factor κ B (NF-κB) activities, thereby attenuating the
proliferation and migration of SK-Hep-1 cells. In conclusion, SOD1
restoration attenuated the tumorigenicity of hepatoma cells.

ABBREVIATIONS ………………... 2
ABSTRACT ………………... 3
INTRODUCTION ………………... 5
MATERIALS AND METHODS ………………... 12
RESULTS ………………... 19
DISCUSSION ………………... 23
FIGURES AND LEGENDS ………………... 26
REFERENCES ………………... 41

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