B型肝炎病毒X蛋白質在肝癌形成過程的角色

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Title:	B型肝炎病毒X蛋白質在肝癌形成過程的角色
Other Titles:	The role of hepatisis B virus X protein in hepatocarcinogenesis
Authors:	王靜琪 Wang, Jing-Chyi
Contributors:	徐士蘭;黃光裕 Hsu, Shih-Lan;Hwang, Guang-Yuh 東海大學生命科學系
Keywords:	B型肝炎病毒X蛋白質;HBx;癌化;動物模式 Hepatitis B virus X protein (HBx);Tumorigenicity;Animal model
Date:	2004
Issue Date:	2011-05-19T06:53:27Z (UTC)
Abstract:	B型肝炎病毒的最小開放讀碼區HBx所轉錄轉譯形成的HBx蛋白質是一多功性的蛋白質，而且HBx目前被認為參與肝癌的形成。然而，HBx在其中的確切角色仍是矛盾的。我們已建立可誘發HBx基因表達的肝細胞株Chang-HBx，和原本的肝細胞株Chang liver cell相比較，Chang-HBx細胞在含血清培養液中的生長速率比Chang liver cell的快，但是在缺乏血清的培養液中，Chang-HBx的生長速率則比Chang liver cell慢。在軟膠細胞群落形成的分析中，Chang-HBx細胞株表現需要附著生長的特性且在BALB/c裸鼠體表下的癌生長測試中，表現HBx蛋白質的Chang-HBx能夠抑制癌的生長。另外，進行細胞流式分析的結果發現，在缺乏血清的培養下，表現HBx蛋白質的早期，Chang-HBx細胞生長會停滯在G1期。因此HBx蛋白質在癌形成過程可能扮演抑制的角色。根據這些現象我們假設：營養不足可能可以作為探討HBx抑制肝癌形成的條件。所以在無血清培養Chang-HBx細胞的初步結果發現，Chang-HBx細胞形態呈現延展的形狀，不像Chang liver cell或生長在血清中Chang-HBx的卵形細胞形態。而且在無血清培養的72小時中，Chang-HBx細胞的細胞週期分子cyclin D1， cdk2和p53的蛋白質表現有變化，而在120小時的無血清培養後，Chang-HBx細胞則有發生apoptosis的DNA斷裂現象。在Chang-HBx細胞形成肝癌組織的蛋白質萃取液則發現，cyclin A、cyclin B、cyclin D1、cdk2、cdk4、p53、Rb2、p21的表現量比Chang的肝癌組織多，此分子堆積現象可能是HBx蛋白質長期表達所導致。 The hepatitis B virus X gene, which is the smallest open reading frame of HBV, encodes the HBx protein, has multiple functions and is involved in hepatocarcinogenesis. However, the exact role of HBx in hepatocarcinogenesis is still controversial. We have established an inducible (tet-off system) HBx-expressing cell line, Chang-HBx. As compared with the original of Chang liver cell line (ATCC CCL13), Chang-HBx grows faster in serum-containing medium but slower in serum-free medium. Chang-HBx colony-formation in soft agar shows an anchorage-demanding character and its tumorigenicity potential in BALB/C nude mice were substantially inhibited. HBx also causes the induction of G1 phase arrest of cell growth in early infection of HBV and therefore plays a negative role in tumorigenicity. The detailed exploration of the roles of HBx in hepatocarcinogenesis was then followed in the aspect of nutrient deficiency. The data show that the cell morphology of Chang-HBx was elongated in serum-free culture medium unlike the oval shape of Chang liver cell or Chang-HBx in 10% fetal calf serum culture medium. Protein expressions of cyclin D1, cdk2, and p53 were also changed in a serum-free 72 hours culture. The apoptosis of these cells did occur in 120 hours culture. Analysis of protein extracts of tumors derived from Chang-HBx cells found that an accumulated expression of cyclin A, cyclin B, cyclin D1, cdk2, cdk4, p53, Rb2, and p21 was observed. The result might be due to the long period expression of HBx protein.
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