探討Arrest defective-1 protein (ARD1)在骨肉瘤細胞侵犯轉移過程中之角色

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題名:	探討Arrest defective-1 protein (ARD1)在骨肉瘤細胞侵犯轉移過程中之角色 The Role of Arrest defective-1 protein (ARD1) in Invasion and Metastasis of Osteosarcoma Cells
作者:	丹芃 Tan, Peng
關鍵詞:	骨肉瘤;N端乙醯基轉移酶;細胞侵犯;骨肉瘤肺轉移;ARD1;Invasion;Metastasis;Osteosarcoma
日期:	2016-06-29
上傳時間:	2018-10-15 10:12:41 (UTC+8)
摘要:	骨肉瘤是一種好發於青少年的癌症，在癌細胞發生肺部遠端轉移後其死亡率便會大大的提昇，目前的治療方式大多以手術切除為主，因患者多為青少年，截肢後對患者未來的生活品質也有很大的影響。本研究之主題為釐清骨肉瘤其發生與轉移之機制探討，希望藉此研究成果於將來可提早發現並減少腫瘤轉移的發生率，藉以提高患者的存活率與癒後生活品質。 Arrest-defective 1 protein (ARD1)一開始被發現在酵母菌中扮演影響著細胞生長發育相關機制的重要調控角色，而後發現ARD1與N-acetyl transferase human (NATH)兩個蛋白質分子共同組合可形成一個複合的結構並具有N端乙醯基轉移酵素的活性，藉此影響到許多生物作用機轉如細胞分化及細胞凋亡等。本篇研究顯示在骨肉瘤細胞株的實驗中證實，抑制ARD1表現可顯著降低骨肉瘤細胞的爬行與侵襲能力，相反的，在ARD1過度表現的轉殖株中則是促進了骨肉瘤細胞的爬行及侵襲能力。藉由動物實驗的研究也同樣印證了ARD1可以調控骨癌細胞肺部轉移的能力。透過骨肉瘤組織晶片的分析上，我們發現相較於正常骨組織，ARD1高度表現於骨肉瘤檢體。我們從蛋白酶晶片的結果則進一步發現ARD1可能透過調控基質金屬蛋白酶2 ( matrix metalloproteinase-2, MMP-2)的表現來影響到骨肉瘤細胞轉移與侵襲的能力。機制上我們發現ARD1可透由和基質金屬蛋白酶2的結合經由ARD1其乙醯基轉移酶的酵素活性來調節MMP-2蛋白之穩定度。此外於臨床檢體中也證實了ARD1表現量確實與MMP-2的表現量有著正相關的趨勢。因此，我們的研究顯示ARD1在骨肉瘤上為一個腫瘤轉移的促進因子，其在骨肉瘤的早期發現與治療上可作為一個新的標的因子。 Osteosarcoma is a type of bone cancer that is often found in teenagers. The prognosis will be poor if the cancer cell has been found to metastasis to lung. The current standard treatment for osteosarcoma is surgical removal which would have greatly impact patient's quality of life. The main focus of this thesis is to elucidate the metastatic mechanisms of osteosarcoma in order to inhibit cancer metastasis to increase the patient's survial rate at earlier stage. Thus, aim to improve the disease’s prognosis and patient’s quality of life. Arrest-defective 1 protein (ARD-1) was first found to play an important role in cell mitosis and growth in yeast. ARD-1 and N-acetyl transferase human (NATH) can form a complex to have activity of N-acetyltransferase to play role in various biological activities such as cell division and apoptosis. Data from in vitro studies has demonstrated that ARD-1 knockdown and overexpression can respectively inhibit and promote the migratory and invasive abilities of osteosarcoma cells. In vivo, we also observed that ARD1 can modulate the metastastic ability of osteosarcoma cells. In clinical sample, the higher expressed ARD-1 was observed in osteosarcoma tissues compared to normal bone tissues. Results from proteinase array showed that ARD-1 can regulate the expression of matrix metalloproteinase-2 (MMP-2) to play an influential role in invasive ability of osteosarcoma cells. Mechanistic investigations found that ARD1 can bind and stabilize the MMP-2 protein dependent on its N-acetyltransferase activity. In conclusion, ARD1 would be a new therapeutic target for treatment of osteosarcoma metastasis.
描述:	碩士委員-楊順發委員-華國泰共同指導教授-溫玉清委員-潘秀玲指導教授-簡銘賢
資料類型:	thesis
顯示於類別:	[臨床醫學研究所] 博碩士論文

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