English  |  正體中文  |  简体中文  |  Items with full text/Total items : 69937/69937 (100%)
Visitors : 23023455      Online Users : 249
RC Version 7.0 © Powered By DSPACE, MIT. Enhanced by NTU Library IR team.
Scope Tips:
  • please add "double quotation mark" for query phrases to get precise results
  • please goto advance search for comprehansive author search
  • Adv. Search
    HomeLoginUploadHelpAboutAdminister Goto mobile version

    Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/69365

    Title: 受體酪氨酸激酶AXL促進肺癌細胞之存活及移行的機制探討;A Study on the mechanism of AXL-mediated cell migration and survival in non-small cell lung cancer
    Authors: 卓俊宇;Cho,Chun-Yu
    Contributors: 生命科學系
    Keywords: 非小細胞肺癌;微型核醣核酸;受體酪氨酸激酶;活性氧化物;non-small-cell lung cancer;microRNA;RTK;reactive oxygen species
    Date: 2016-01-21
    Issue Date: 2016-03-17 19:10:43 (UTC+8)
    Publisher: 國立中央大學
    Abstract: AXL是一種受體酪氨酸激酶,在許多癌細胞中都有高度表現。AXL不僅在癌症侵襲/轉移和抗藥性扮演重要的角色,也被證實與癌症的淋巴轉移及臨床分期有關。有趣的是,在癌症患者中,常見AXL過度表現卻沒有觀察到AXL突變,顯示探討其基因調控及活化的機制是非常重要的課題。微型核糖核酸 (miRNA)屬於非編碼RNA,可以藉由和目標基因之mRNA的3’端非轉譯區 (3’-UTR)結合,進而影響其表現。異常的miRNA表現和癌細胞的凋亡、侵犯及轉移有關,但AXL與miRNA之間的調控機制卻少有人探討。另一方面,在癌細胞中,持續性氧化壓力普遍存在;異常的活性氧物質生成已知與癌症的惡化、轉移及抗藥性有關。AXL的大量表現及異常的活性氧物質生成常是造成細胞癌化和增加癌細胞之移行能力的原因。然而,對於癌細胞移行能力的研究上,顯少有文獻探討AXL和活性氧物質之間的關連性。在我們的研究中,我們發現AXL可以通過JNK/ELK1/miR-34a信息傳遞路徑,透由AXL mRNA的3′-UTR特定位置抑制其自身的表現。此外,我們也發現AXL的配體GAS6和AXL的激酶活化區對此負迴饋調控是重要的。這些結果顯示,此一負迴饋調控機制對於維持AXL在癌細胞中的穩定表達水平、以及可能有助癌細胞抵抗凋亡的功能上佔有重要的角色。同時我們也觀察到活性氧物質可以造成AXL的磷酸化及增加癌細胞的移行能力,主要是透由PI3K/AKT1/RAC1的訊息傳遞路徑,而延長磷酸化之AKT的半衰期。總括來說,在腫瘤惡化進展研究上,我們提供新的可能分子機制,釐清AXL所導致的癌細胞存活及移行能力,可對未來的癌症治療提供一個可行的分子標的。;The AXL receptor tyrosine kinase is frequently overexpressed in cancers and not only is crucial in the in vitro invasiveness but also may play an important role in cancer progression. Interestingly, no AXL mutations have been reported in cancers, the mechanism of its expression regulation/activation is therefore of great importance. MicroRNAs (miRNAs) are an abundant class of non-coding RNAs that are involved in post-transcriptional regulation of gene expression to either inhibit mRNA translation or promote its degradation by targeting the 3’-UTR and control a wide range of biological processes that represent the hallmarks of cancer, such as apoptosis, invasion, and metastasis. While mechanisms of miRNA-mediated AXL expression appear important, only a few have been reported. On the other hand, persistent oxidative stress, i.e., abnormal generation of reactive oxygen species (ROS), is common in cancer cells and has been known to be associated with malignant phenotypes, such as chemotherapy resistance and metastasis. Both overexpression of AXL and abnormal ROS elevation have been linked to cell transformation and increased cell motility. However, the relationship between AXL and ROS in malignant cells motility has not been previously evaluated. In this study, we show that AXL up-regulates miR-34a expression via the JNK/ELK1 signaling pathway and that miR-34a consequently returns to inhibit AXL expression via binding to AXL’s mRNA 3’-UTR. Additionally, both the GAS6-binding domain and the kinase domain of AXL are crucial for this auto-regulation. These results demonstrate that this negative regulatory loop may play an important role in maintaining a balanced AXL expression and that malfunction of this regulatory loop may contribute to apoptosis resistance and progression of cancer cells. Moreover, we also observed that oxidative stress could activate AXL phosphorylation to synergistically enhance cell migration via a PI3K/AKT1/RAC1-dependent pathway. The kinase activity of AXL is required for the AXL-mediated cell migration and prolongs the half-life of phospho-AKT under oxidative stress. Together, elucidation of AXL regulation in AXL-related cells survival/migration may provide new molecular insights into the mechanisms underlying tumor progression and may provide a novel opportunity for developing AXL-targeted anti-cancer therapies.
    Appears in Collections:[生命科學研究所 ] 博碩士論文

    Files in This Item:

    File Description SizeFormat

    All items in NCUIR are protected by copyright, with all rights reserved.

    社群 sharing

    ::: Copyright National Central University. | 國立中央大學圖書館版權所有 | 收藏本站 | 設為首頁 | 最佳瀏覽畫面: 1024*768 | 建站日期:8-24-2009 :::
    DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - Feedback  - 隱私權政策聲明