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標題: AIF基因表現與非小細胞肺癌抗藥性之研究
AIF gene expression and drug resistance in NSCLC.
作者: 陳文恆
Chen, Wen-Heng
Contributors: 周寬基
Kuan-Chih Chow
國立中興大學
關鍵字: AIF;non-small cell lung cancer;drug resistance
非小細胞肺癌;抗藥性
日期: 2005
Issue Date: 2012-09-04 10:45:57 (UTC+8)
Publisher: 生物醫學研究所
摘要: 細胞凋亡 (apoptosis)為一有計畫性的細胞死亡機制,對於維持整體細胞的恆定及在胚胎發育的過程中都扮演著相當重要的角色。AIF是一個在演化過程中具有高度保留性的粒線體間質蛋白,其可以不需要經由caspase的活化而直接引起細胞凋亡。當細胞接受到細胞凋亡的刺激時,AIF會由粒線體中被釋放出來隨即進入到細胞核中。在細胞核中AIF可以直接與DNA結合,接著引起大規模的DNA斷裂及染色質的濃縮,最終導致細胞走向凋亡。
在本論文中,我們發現在部分的非小細胞肺癌細胞株及肺癌檢體中AIF有著過量表現的情形。而在肺癌檢體中,AIF過量表現的比例又與臨床上接受化學藥物治療有效的比例相似。同時,我們以化療藥物cisplatin進行細胞毒性測試時,AIF表現量較低的細胞株又有著明顯較高的藥物抗藥性。因此,AIF表現量的高低或許可以成為一個臨床上的指標,用來評估非小細胞肺癌化學治療之預後。
此外,我們更藉由酵母菌雙雜合系統,發現一個能與AIF交互作用的蛋白Rad23A。無論是在細胞質及細胞核中都可以發現兩者的結合。但是,目前對於AIF和Rad23A之間的關係,我們所知仍然相當有限,有待今後更進一步的研究。
Apoptosis, a tightly controlled multi-step mechanism of cell death that involves a battery of expressed proteins, plays an important role in the regulation of normal tissue homeostasis and embryonic development. Among these, apoptosis-inducing factor (AIF), a phylogenetically conserved mitochondrial intermembrane space protein, is the one that has been shown to induce apoptosis via a caspase-independent pathway. In particular, in response to proapoptotic signaling, AIF could be released from mitochondria and then translocated to the nucleus. In the nucleus, AIF acts directly on nuclear DNA and induces large-scale DNA fragmentation and chromosome condensation, which subsequently result in apoptosis. However, expression of AIF in lung cancer cells was not previously examined.
We therefore cloned monoclonal antibodies to AIF, and our results showed that AIF was overexpressed in lung cancer cell lines and tissue specimens. Interestingly, ratio of AIF overexpression correlated with chemosensitivity. In vitro, cell lines that have lower AIF content are more resistant to cisplatin. Hence, our results suggest that level of AIF expression may be helpful for assessing the effect of chemotherapy in patients with non-small cell lung cancer (NSCLC).
Furthermore, by yeast two hybrid system, we found that Rad23 homolog A could interact with AIF both in cytosolic and nuclear extracts. Nonetheless, relationship between AIF and Rad23A is not clear and it is worth investigating in the future.
Appears in Collections:[依資料類型分類] 碩博士論文

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