博碩士論文 100284002 詳細資訊




以作者查詢圖書館館藏 以作者查詢臺灣博碩士 以作者查詢全國書目 勘誤回報 、線上人數:8 、訪客IP:35.172.233.215
姓名 卓俊宇(Chun-Yu Cho)  查詢紙本館藏   畢業系所 生命科學系
論文名稱 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)
相關論文
★ Thirst control of water-seeking behavior in Drosophila★ MyoD對於PGC-1α 基因表現之調控機制
★ 雄性素受體對於肌肉前驅細胞決定的功用★ Nanog和Oct4表現對肌肉分化之影響
★ 大量表現幹細胞專有轉錄因子抑制肌肉細胞走向分化★ FOXOs 轉錄調控因子家族對肌肉細胞末期分化的影響
★ 大量表現 Oct4 與 Nanog 抑制肌纖維母細胞 C2C12 分化★ 在終極肌肉分化時,肌肉性bHLH轉錄因子對PGC-1α的調控
★ FoxOs 大量表現對肌肉細胞末期分化的影響★ 觀察肌肉生成轉錄因子如何調控 M- 和N- cadherin 表現
★ Oc4和Nanog共同抑制末端肌肉分化★ FoxO6在肌原母細胞中的代謝及分化中所扮演的角色
★ PGC-1α 與 Stra13 間之交互作用★ 探討大量表現 FoxO6 對肌肉終極分化的影響以及尋找 FoxO6 蛋白質在 PGC-1 alpha 啟動子上的結合位
★ 探討丙戊酸 (Valporic acid) 於肌肉細胞中活化 Oct4 promoter 的機制★ 探討小鼠骨骼肌中FoxO6的表現情形
檔案 [Endnote RIS 格式]    [Bibtex 格式]    [相關文章]   [文章引用]   [完整記錄]   [館藏目錄]   [檢視]  [下載]
  1. 本電子論文使用權限為同意立即開放。
  2. 已達開放權限電子全文僅授權使用者為學術研究之目的,進行個人非營利性質之檢索、閱讀、列印。
  3. 請遵守中華民國著作權法之相關規定,切勿任意重製、散佈、改作、轉貼、播送,以免觸法。

摘要(中) 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。
摘要(英) 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.
關鍵字(中) ★ 非小細胞肺癌
★ 微型核醣核酸
★ 受體酪氨酸激酶
★ 活性氧化物
關鍵字(英) ★ non-small-cell lung cancer
★ microRNA
★ RTK
★ reactive oxygen species
論文目次 Table of contents

Declaration IV
Publications arising from this thesis V
(A) Referred papers: V
(B) Abstracts presented in meetings: V
中文摘要 VI
Abstract VII
Acknowledgments IX
Abbreviation XI
Table of contents I
Chapter I: Introduction 1
Epidemiology of lung cancer 1
Receptor tyrosine kinase (RTK), AXL 1
Figure I-1 Schematic presentation of the TAM family receptors. 3
Figure I-2 Schematic presentation of the AXL signaling pathways. 4
MicroRNA and RTK in cancers 5
Figure I-3. Genomic loci structure of the human miR-34a and miR-34b/c genes. 6
Figure I-4. Sequence of the AXL mRNA 3’-UTR with the miR-34a binding site indicated. 7
RNA interference mechanisms and applications 7
Reactive oxygen species (ROS) and RTK 8
Figure I-5. Biological stimuli associated with the generation of reactive oxygen species (ROS). 11
Chapter II: Materials and Methods 14
Cell lines, transfection, siRNA 14
Identification of miRNA binding sites 14
qRT-PCR for microRNAs quantification 15
Plasmids construction 15
Microarray analysis of AXL-responsive miRNAs 16
Reagents 17
Chromatin immunoprecipitation (CHIP) assay 17
Cell-cycle analysis 18
Apoptosis analysis by flow cytometry 18
Cell migration (wound-healing) assay 19
Cell migration (trans-well) assay 19
Protein extraction and Western blot analysis 20
Analysis of p-AXL by immunoprecipitation (IP)–Western blots 21
Detection of the intracellular ROS levels 21
Silencing of AKT1 and AKT2 expression by small interfering RNA (siRNA) 22
RAC1 constructs and RAC1 immunoprecipitation assay 22
Statistical analysis 23
Chapter III: Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells 23
Rationale 23
Results 25
AXL is negatively regulated in a post-transcriptional feedback loop 25
The AXL kinase domain and auto-phosphorylation site Y779 of AXL are crucial to the feedback regulation 26
The AXL ligand GAS6 is important for the negative feedback loop 27
Prediction of microRNAs that target AXL 28
miR-34a targets the 3’-UTR of AXL mRNA and inhibits its expression 29
JNK-ELK1 signal pathway is involved in the regulation of miR-34a by AXL 30
ELK1 promotes apoptosis in part through inhibition of AXL kinase activity 33
Discussion 34
Figures 41
Table III-1. Fold decrease of endogenous AXL mRNA expression by AXL over-expression, as revealed by microarray analysis 65
Table III-2. Putative microRNAs targeting AXL 66
Table III-3. Relative increase in miRNA levels upon AXL over-expression, as revealed by microarray analysis 67
Table III-4. 68
Chapter IV: Oxidative stress enhances AXL-mediated cell migration through an AKT1/RAC1-dependent mechanism 70
Rationale 70
Results 72
Intracellular ROS levels correlate with AXL expression and malignant phenotypes 72
AXL -mediated RAC1 activation leads to ROS accumulation 73
H2O2 induces AXL tyrosine phosphorylation and synergistically enhances AXL -mediated migration 73
RAC1 is required for AXL-mediated cell migration enhanced by H2O2 treatment through the PI3K/Akt pathway 74
Roles of various AXL domains in ROS-enhanced cell motility and Akt signaling 75
AKT1 is required for ROS-induced RAC1 activation and cell motility 77
Discussion 78
Figures 85
Figure IV-1. AXL kinase activity increases intracellular ROS. 85
Figure IV-2. Intracellular ROS levels positively links to the malignant phenotypes. 87
Figure IV-3. The steady-state levels of MnSOD, Cu/ZnSOD and catalase (CAT) are similar among cell lines. 88
Figure IV-4. The steady-state levels of GAS6 are low and show no difference among these cells. 89
Figure IV-5. AXL phosphorylation is required for activation of RAC1. 91
Figure IV-6. AXL-mediated cell migration was synergistically enhanced by H2O2 treatment. 93
Figure IV-8. The MAPK pathways are not involved in AXL-mediated migration under oxidative condition. 97
Figure IV-9. Inhibition of ROS level leads to decreased Akt phosphorylation and attenuates cell motility. 98
Figure IV-11. Expression levels of AKT1, AKT2 and AXL in the CL1 sublines by Western blot analysis. 102
Figure IV-13. Inhibitory effect of R428 on AXL activation. 105
Chapter V: General discussion and future work 108
NF-kB, miR-34a and RAC1 in drug resistance 108
AXL and miRNA in carcinogenesis 109
Identification of novel therapeutic miRNAs 111
Figure V-1. MiR-449 cluster miRs down-regulate expression of several G1 phase proteins in NSCLC cells. 114
Therapeutic opportunities using new AXL targets 115
Figure V-2. PTBP1 regulates AXL mRNA expression. 117
Figure V-3. Expression of PTBP1 and its involvement in AXL regulation. 118
References 119
參考文獻 Acunzo M, Romano G, Palmieri D, Lagana A, Garofalo M, Balatti V, Drusco A, Chiariello M, Nana-Sinkam P, Croce CM. 2013. Cross-talk between MET and EGFR in non-small cell lung cancer involves miR-27a and Sprouty2. Proceedings of the National Academy of Sciences of the United States of America 110: 8573-8578.
Alberg AJ, Brock MV, Samet JM. 2005. Epidemiology of lung cancer: looking to the future. J Clin Oncol 23: 3175-3185.
Alexandrova AY, Kopnin PB, Vasiliev JM, Kopnin BP. 2006. ROS up-regulation mediates Ras-induced changes of cell morphology and motility. Exp Cell Res 312: 2066-2073.
Anwar A, Keating AK, Joung D, Sather S, Kim GK, Sawczyn KK, Brandao L, Henson PM, Graham DK. 2009. Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress. J Leukoc Biol 86: 73-79.
Bae YS, Kang SW, Seo MS, Baines IC, Tekle E, Chock PB, Rhee SG. 1997. Epidermal growth factor (EGF)-induced generation of hydrogen peroxide. Role in EGF receptor-mediated tyrosine phosphorylation. J Biol Chem 272: 217-221.
Bae YS, Sung JY, Kim OS, Kim YJ, Hur KC, Kazlauskas A, Rhee SG. 2000. Platelet-derived growth factor-induced H(2)O(2) production requires the activation of phosphatidylinositol 3-kinase. J Biol Chem 275: 10527-10531.
Balsara BR, Pei J, Mitsuuchi Y, Page R, Klein-Szanto A, Wang H, Unger M, Testa JR. 2004. Frequent activation of AKT in non-small cell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 25: 2053-2059.
Bartel DP. 2004. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116: 281-297.
Bellosta P, Costa M, Lin DA, Basilico C. 1995. The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding. Molecular and cellular biology 15: 614-625.
Benedettini E, Sholl LM, Peyton M, Reilly J, Ware C, Davis L, Vena N, Bailey D, Yeap BY, Fiorentino M, et al. 2010. Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. The American journal of pathology 177: 415-423.
Bommer GT, Gerin I, Feng Y, Kaczorowski AJ, Kuick R, Love RE, Zhai Y, Giordano TJ, Qin ZS, Moore BB, et al. 2007. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Current biology : CB 17: 1298-1307.
Bou Kheir T, Futoma-Kazmierczak E, Jacobsen A, Krogh A, Bardram L, Hother C, Gronbaek K, Federspiel B, Lund AH, Friis-Hansen L. 2011. miR-449 inhibits cell proliferation and is down-regulated in gastric cancer. Molecular cancer 10: 29.
Bouchie A. 2013. First microRNA mimic enters clinic. Nature biotechnology 31: 577.
Boysen J, Sinha S, Price-Troska T, Warner SL, Bearss DJ, Viswanatha D, Shanafelt TD, Kay NE, Ghosh AK. 2014. The tumor suppressor axis p53/miR-34a regulates Axl expression in B-cell chronic lymphocytic leukemia: implications for therapy in p53-defective CLL patients. Leukemia 28: 451-455.
Brognard J, Clark AS, Ni Y, Dennis PA. 2001. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res 61: 3986-3997.
Cahill S, Smyth P, Finn SP, Denning K, Flavin R, O′Regan EM, Li J, Potratz A, Guenther SM, Henfrey R, et al. 2006. Effect of ret/PTC 1 rearrangement on transcription and post-transcriptional regulation in a papillary thyroid carcinoma model. Molecular cancer 5: 70.
Calin GA, Croce CM. 2006. MicroRNA signatures in human cancers. Nature reviews Cancer 6: 857-866.
Cavigelli M, Dolfi F, Claret FX, Karin M. 1995. Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. The EMBO journal 14: 5957-5964.
Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, et al. 2007. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Molecular cell 26: 745-752.
Chen H, Lin YW, Mao YQ, Wu J, Liu YF, Zheng XY, Xie LP. 2012. MicroRNA-449a acts as a tumor suppressor in human bladder cancer through the regulation of pocket proteins. Cancer letters 320: 40-47.
Chen QY, Xu LQ, Jiao DM, Yao QH, Wang YY, Hu HZ, Wu YQ, Song J, Yan J, Wu LJ. 2011. Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs. International journal of molecular medicine 28: 769-776.
Chin YR, Toker A. 2009. Function of Akt/PKB signaling to cell motility, invasion and the tumor stroma in cancer. Cell Signal 21: 470-476.
Chou YT, Lin HH, Lien YC, Wang YH, Hong CF, Kao YR, Lin SC, Chang YC, Lin SY, Chen SJ, et al. 2010. EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF. Cancer research 70: 8822-8831.
Christoffersen NR, Shalgi R, Frankel LB, Leucci E, Lees M, Klausen M, Pilpel Y, Nielsen FC, Oren M, Lund AH. 2010. p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell death and differentiation 17: 236-245.
Chung BI, Malkowicz SB, Nguyen TB, Libertino JA, McGarvey TW. 2003. Expression of the proto-oncogene Axl in renal cell carcinoma. DNA Cell Biol 22: 533-540.
Corney DC, Hwang CI, Matoso A, Vogt M, Flesken-Nikitin A, Godwin AK, Kamat AA, Sood AK, Ellenson LH, Hermeking H, et al. 2010. Frequent downregulation of miR-34 family in human ovarian cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 16: 1119-1128.
Craven RJ, Xu LH, Weiner TM, Fridell YW, Dent GA, Srivastava S, Varnum B, Liu ET, Cance WG. 1995. Receptor tyrosine kinases expressed in metastatic colon cancer. Int J Cancer 60: 791-797.
Davalos AR, Coppe JP, Campisi J, Desprez PY. 2010. Senescent cells as a source of inflammatory factors for tumor progression. Cancer metastasis reviews 29: 273-283.
Delhalle S, Deregowski V, Benoit V, Merville MP, Bours V. 2002. NF-kappaB-dependent MnSOD expression protects adenocarcinoma cells from TNF-alpha-induced apoptosis. Oncogene 21: 3917-3924.
Demarchi F, Verardo R, Varnum B, Brancolini C, Schneider C. 2001. Gas6 anti-apoptotic signaling requires NF-kappa B activation. The Journal of biological chemistry 276: 31738-31744.
Dutta KK, Zhong Y, Liu YT, Yamada T, Akatsuka S, Hu Q, Yoshihara M, Ohara H, Takehashi M, Shinohara T, et al. 2007. Association of microRNA-34a overexpression with proliferation is cell type-dependent. Cancer science 98: 1845-1852.
Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, et al. 2007. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316: 1039-1043.
Esme H, Cemek M, Sezer M, Saglam H, Demir A, Melek H, Unlu M. 2008. High levels of oxidative stress in patients with advanced lung cancer. Respirology 13: 112-116.
Esquela-Kerscher A, Slack FJ. 2006. Oncomirs - microRNAs with a role in cancer. Nature reviews Cancer 6: 259-269.
Fang Y, Xue JL, Shen Q, Chen J, Tian L. 2012. MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology 55: 1852-1862.
Farooqui R, Zhu S, Fenteany G. 2006. Glycogen synthase kinase-3 acts upstream of ADP-ribosylation factor 6 and Rac1 to regulate epithelial cell migration. Exp Cell Res 312: 1514-1525.
Ferraro D, Corso S, Fasano E, Panieri E, Santangelo R, Borrello S, Giordano S, Pani G, Galeotti T. 2006. Pro-metastatic signaling by c-Met through RAC-1 and reactive oxygen species (ROS). Oncogene 25: 3689-3698.
Fridell YW, Jin Y, Quilliam LA, Burchert A, McCloskey P, Spizz G, Varnum B, Der C, Liu ET. 1996. Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is responsible for the biological consequences induced by the Axl receptor tyrosine kinase. Molecular and cellular biology 16: 135-145.
Gallicchio M, Mitola S, Valdembri D, Fantozzi R, Varnum B, Avanzi GC, Bussolino F. 2005. Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood 105: 1970-1976.
Garofalo M, Romano G, Di Leva G, Nuovo G, Jeon YJ, Ngankeu A, Sun J, Lovat F, Alder H, Condorelli G, et al. 2012. EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers. Nature medicine 18: 74-82.
Gastonguay A, Berg T, Hauser AD, Schuld N, Lorimer E, Williams CL. 2012. The role of Rac1 in the regulation of NF-kappaB activity, cell proliferation, and cell migration in non-small cell lung carcinoma. Cancer biology & therapy 13: 647-656.
Georgescu MM, Kirsch KH, Shishido T, Zong C, Hanafusa H. 1999. Biological effects of c-Mer receptor tyrosine kinase in hematopoietic cells depend on the Grb2 binding site in the receptor and activation of NF-kappaB. Molecular and cellular biology 19: 1171-1181.
Gougelet A, Sartor C, Bachelot L, Godard C, Marchiol C, Renault G, Tores F, Nitschke P, Cavard C, Terris B, et al. 2015. Antitumour activity of an inhibitor of miR-34a in liver cancer with beta-catenin-mutations. Gut.
Gupta A, Srivastava S, Prasad R, Natu SM, Mittal B, Negi MP, Srivastava AN. 2010. Oxidative stress in non-small cell lung cancer patients after chemotherapy: association with treatment response. Respirology 15: 349-356.
Hafizi S, Dahlback B. 2006. Signalling and functional diversity within the Axl subfamily of receptor tyrosine kinases. Cytokine & growth factor reviews 17: 295-304.
Hafizi S, Ibraimi F, Dahlback B. 2005. C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration. FASEB J 19: 971-973.
Hasanbasic I, Cuerquis J, Varnum B, Blostein MD. 2004. Intracellular signaling pathways involved in Gas6-Axl-mediated survival of endothelial cells. Am J Physiol Heart Circ Physiol 287: H1207-1213.
Heiring C, Dahlback B, Muller YA. 2004. Ligand recognition and homophilic interactions in Tyro3: structural insights into the Axl/Tyro3 receptor tyrosine kinase family. The Journal of biological chemistry 279: 6952-6958.
Hempel N, Ye H, Abessi B, Mian B, Melendez JA. 2009. Altered redox status accompanies progression to metastatic human bladder cancer. Free Radic Biol Med 46: 42-50.
Hermeking H. 2010. The miR-34 family in cancer and apoptosis. Cell death and differentiation 17: 193-199.
Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W, Duan M, Torneros A, Yu J, Heckrodt TJ, et al. 2010. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer research 70: 1544-1554.
Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, Lai GM, Chuang SE. 2008. Receptor tyrosine kinase AXL is induced by chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer letters 268: 314-324.
Huang JS, Cho CY, Hong CC, Yan MD, Hsieh MC, Lay JD, Lai GM, Cheng AL, Chuang SE. 2013. Oxidative stress enhances Axl-mediated cell migration through an Akt1/Rac1-dependent mechanism. Free radical biology & medicine 65: 1246-1256.
Huang Q, Sheibani N. 2008. High glucose promotes retinal endothelial cell migration through activation of Src, PI3K/Akt1/eNOS, and ERKs. Am J Physiol Cell Physiol 295: C1647-1657.
Imam JS, Plyler JR, Bansal H, Prajapati S, Bansal S, Rebeles J, Chen HI, Chang YF, Panneerdoss S, Zoghi B, et al. 2012. Genomic Loss of Tumor Suppressor miRNA-204 Promotes Cancer Cell Migration and Invasion by Activating AKT/mTOR/Rac1 Signaling and Actin Reorganization. PLoS One 7: e52397.
Inui M, Martello G, Piccolo S. 2010. MicroRNA control of signal transduction. Nature reviews Molecular cell biology 11: 252-263.
Inumaru J, Nagano O, Takahashi E, Ishimoto T, Nakamura S, Suzuki Y, Niwa S, Umezawa K, Tanihara H, Saya H. 2009. Molecular mechanisms regulating dissociation of cell-cell junction of epithelial cells by oxidative stress. Genes Cells 14: 703-716.
Jemal A, Siegel R, Xu J, Ward E. 2010. Cancer statistics, 2010. CA Cancer J Clin 60: 277-300.
John B, Enright AJ, Aravin A, Tuschl T, Sander C, Marks DS. 2004. Human MicroRNA targets. PLoS Biol 2: e363.
Kaller M, Liffers ST, Oeljeklaus S, Kuhlmann K, Roh S, Hoffmann R, Warscheid B, Hermeking H. 2011. Genome-wide characterization of miR-34a induced changes in protein and mRNA expression by a combined pulsed SILAC and microarray analysis. Mol Cell Proteomics 10: M111 010462.
Kefas B, Godlewski J, Comeau L, Li Y, Abounader R, Hawkinson M, Lee J, Fine H, Chiocca EA, Lawler S, et al. 2008. microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. Cancer research 68: 3566-3572.
Kim D, Song J, Kim S, Park HM, Chun CH, Sonn J, Jin EJ. 2012. MicroRNA-34a modulates cytoskeletal dynamics through regulating RhoA/Rac1 cross-talk in chondroblasts. The Journal of biological chemistry 287: 12501-12509.
Komatsu D, Kato M, Nakayama J, Miyagawa S, Kamata T. 2008. NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor expression. Oncogene 27: 4724-4732.
Konishi A, Aizawa T, Mohan A, Korshunov VA, Berk BC. 2004. Hydrogen peroxide activates the Gas6-Axl pathway in vascular smooth muscle cells. J Biol Chem 279: 28766-28770.
Koorstra JB, Karikari CA, Feldmann G, Bisht S, Rojas PL, Offerhaus GJ, Alvarez H, Maitra A. 2009. The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biol Ther 8: 618-626.
Kumar B, Koul S, Khandrika L, Meacham RB, Koul HK. 2008. Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. Cancer Res 68: 1777-1785.
Lay JD, Hong CC, Huang JS, Yang YY, Pao CY, Liu CH, Lai YP, Lai GM, Cheng AL, Su IJ, et al. 2007. Sulfasalazine suppresses drug resistance and invasiveness of lung adenocarcinoma cells expressing AXL. Cancer research 67: 3878-3887.
Lee JH, Voortman J, Dingemans AM, Voeller DM, Pham T, Wang Y, Giaccone G. 2011. MicroRNA expression and clinical outcome of small cell lung cancer. PloS one 6: e21300.
Lee WP, Wen Y, Varnum B, Hung MC. 2002. Akt is required for Axl-Gas6 signaling to protect cells from E1A-mediated apoptosis. Oncogene 21: 329-336.
Lee YS, Dutta A. 2009. MicroRNAs in cancer. Annual review of pathology 4: 199-227.
Lewis BP, Shih IH, Jones-Rhoades MW, Bartel DP, Burge CB. 2003. Prediction of mammalian microRNA targets. Cell 115: 787-798.
Li J, Wang K, Chen X, Meng H, Song M, Wang Y, Xu X, Bai Y. 2012. Transcriptional activation of microRNA-34a by NF-kappa B in human esophageal cancer cells. BMC molecular biology 13: 4.
Li LC, Okino ST, Zhao H, Pookot D, Place RF, Urakami S, Enokida H, Dahiya R. 2006. Small dsRNAs induce transcriptional activation in human cells. Proceedings of the National Academy of Sciences of the United States of America 103: 17337-17342.
Li N, Fu H, Tie Y, Hu Z, Kong W, Wu Y, Zheng X. 2009a. miR-34a inhibits migration and invasion by down-regulation of c-Met expression in human hepatocellular carcinoma cells. Cancer letters 275: 44-53.
Li W, Xie L, He X, Li J, Tu K, Wei L, Wu J, Guo Y, Ma X, Zhang P, et al. 2008. Diagnostic and prognostic implications of microRNAs in human hepatocellular carcinoma. International journal of cancer Journal international du cancer 123: 1616-1622.
Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, Marcinkiewicz L, Jiang J, Yang Y, Schmittgen TD, et al. 2009b. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer research 69: 7569-7576.
Liang Y, McDonnell S, Clynes M. 2002. Examining the relationship between cancer invasion/metastasis and drug resistance. Curr Cancer Drug Targets 2: 257-277.
Linger RM, Keating AK, Earp HS, Graham DK. 2008. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res 100: 35-83.
Liu L, Greger J, Shi H, Liu Y, Greshock J, Annan R, Halsey W, Sathe GM, Martin AM, Gilmer TM. 2009. Novel Mechanism of Lapatinib Resistance in HER2-Positive Breast Tumor Cells: Activation of AXL. Cancer Research 69: 6871-6878.
Lize M, Klimke A, Dobbelstein M. 2011. MicroRNA-449 in cell fate determination. Cell Cycle 10: 2874-2882.
Lize M, Pilarski S, Dobbelstein M. 2010. E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis. Cell death and differentiation 17: 452-458.
Lodygin D, Tarasov V, Epanchintsev A, Berking C, Knyazeva T, Korner H, Knyazev P, Diebold J, Hermeking H. 2008. Inactivation of miR-34a by aberrant CpG methylation in multiple types of cancer. Cell Cycle 7: 2591-2600.
Luo W, Huang B, Li Z, Li H, Sun L, Zhang Q, Qiu X, Wang E. 2013. MicroRNA-449a is downregulated in non-small cell lung cancer and inhibits migration and invasion by targeting c-Met. PloS one 8: e64759.
Ma Y, Qin H, Cui Y. 2013. MiR-34a targets GAS1 to promote cell proliferation and inhibit apoptosis in papillary thyroid carcinoma via PI3K/Akt/Bad pathway. Biochemical and biophysical research communications 441: 958-963.
Mackiewicz M, Huppi K, Pitt JJ, Dorsey TH, Ambs S, Caplen NJ. 2011. Identification of the receptor tyrosine kinase AXL in breast cancer as a target for the human miR-34a microRNA. Breast Cancer Res Treat 130: 663-679.
Macleod K, Mullen P, Sewell J, Rabiasz G, Lawrie S, Miller E, Smyth JF, Langdon SP. 2005. Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. Cancer Res 65: 6789-6800.
Meric F, Lee WP, Sahin A, Zhang H, Kung HJ, Hung MC. 2002. Expression profile of tyrosine kinases in breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 8: 361-367.
Meyer AS, Miller MA, Gertler FB, Lauffenburger DA. 2013. The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells. Science signaling 6: ra66.
Migliore C, Petrelli A, Ghiso E, Corso S, Capparuccia L, Eramo A, Comoglio PM, Giordano S. 2008. MicroRNAs impair MET-mediated invasive growth. Cancer research 68: 10128-10136.
Mudduluru G, Ceppi P, Kumarswamy R, Scagliotti GV, Papotti M, Allgayer H. 2011. Regulation of Axl receptor tyrosine kinase expression by miR-34a and miR-199a/b in solid cancer. Oncogene 30: 2888-2899.
Mudduluru G, Vajkoczy P, Allgayer H. 2010. Myeloid zinc finger 1 induces migration, invasion, and in vivo metastasis through Axl gene expression in solid cancer. Molecular cancer research : MCR 8: 159-169.
Nielsen-Preiss SM, Allen MP, Xu M, Linseman DA, Pawlowski JE, Bouchard RJ, Varnum BC, Heidenreich KA, Wierman ME. 2007. Adhesion-related kinase induction of migration requires phosphatidylinositol-3-kinase and ras stimulation of rac activity in immortalized gonadotropin-releasing hormone neuronal cells. Endocrinology 148: 2806-2814.
Nishikawa M. 2008. Reactive oxygen species in tumor metastasis. Cancer Lett 266: 53-59.
Noonan EJ, Place RF, Pookot D, Basak S, Whitson JM, Hirata H, Giardina C, Dahiya R. 2009. miR-449a targets HDAC-1 and induces growth arrest in prostate cancer. Oncogene 28: 1714-1724.
Novo E, Parola M. 2012. The role of redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis & tissue repair 5: S4.
O′Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, Prokop C, Espinosa R, 3rd, Le Beau MM, Earp HS, Liu ET. 1991. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Molecular and cellular biology 11: 5016-5031.
Onishi K, Higuchi M, Asakura T, Masuyama N, Gotoh Y. 2007. The PI3K-Akt pathway promotes microtubule stabilization in migrating fibroblasts. Genes Cells 12: 535-546.
Ott M, Litzenburger UM, Sahm F, Rauschenbach KJ, Tudoran R, Hartmann C, Marquez VE, von Deimling A, Wick W, Platten M. 2012. Promotion of glioblastoma cell motility by enhancer of zeste homolog 2 (EZH2) is mediated by AXL receptor kinase. PloS one 7: e47663.
Pani G, Colavitti R, Bedogni B, Anzevino R, Borrello S, Galeotti T. 2000. A redox signaling mechanism for density-dependent inhibition of cell growth. J Biol Chem 275: 38891-38899.
Park SJ, Kim YT, Jeon YJ. 2012. Antioxidant dieckol downregulates the Rac1/ROS signaling pathway and inhibits Wiskott-Aldrich syndrome protein (WASP)-family verprolin-homologous protein 2 (WAVE2)-mediated invasive migration of B16 mouse melanoma cells. Mol Cells 33: 363-369.
Pelicano H, Carney D, Huang P. 2004. ROS stress in cancer cells and therapeutic implications. Drug Resist Updat 7: 97-110.
Place RF, Li LC, Pookot D, Noonan EJ, Dahiya R. 2008. MicroRNA-373 induces expression of genes with complementary promoter sequences. Proceedings of the National Academy of Sciences of the United States of America 105: 1608-1613.
Qian Y, Zhong X, Flynn DC, Zheng JZ, Qiao M, Wu C, Dedhar S, Shi X, Jiang BH. 2005. ILK mediates actin filament rearrangements and cell migration and invasion through PI3K/Akt/Rac1 signaling. Oncogene 24: 3154-3165.
Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, et al. 2005. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436: 123-127.
Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M. 2007. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Molecular cell 26: 731-743.
Reddy SD, Ohshiro K, Rayala SK, Kumar R. 2008. MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions. Cancer research 68: 8195-8200.
Rho JK, Choi YJ, Kim SY, Kim TW, Choi EK, Yoon SJ, Park BM, Park E, Bae JH, Choi CM, et al. 2014. MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation. Cancer research 74: 253-262.
Ribeiro J, Marinho-Dias J, Monteiro P, Loureiro J, Baldaque I, Medeiros R, Sousa H. 2015. miR-34a and miR-125b Expression in HPV Infection and Cervical Cancer Development. BioMed research international 2015: 304584.
Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, et al. 2007. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131: 1190-1203.
Rochlitz C, Lohri A, Bacchi M, Schmidt M, Nagel S, Fopp M, Fey MF, Herrmann R, Neubauer A. 1999. Axl expression is associated with adverse prognosis and with expression of Bcl-2 and CD34 in de novo acute myeloid leukemia (AML): results from a multicenter trial of the Swiss Group for Clinical Cancer Research (SAKK). Leukemia 13: 1352-1358.
Sainaghi PP, Castello L, Bergamasco L, Galletti M, Bellosta P, Avanzi GC. 2005. Gas6 induces proliferation in prostate carcinoma cell lines expressing the Axl receptor. J Cell Physiol 204: 36-44.
Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Gohring W, Ullrich A, Timpl R, Hohenester E. 2006. Structural basis for Gas6-Axl signalling. EMBO J 25: 80-87.
Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS, Wu CW. 2005. Expression of axl in lung adenocarcinoma and correlation with tumor progression. Neoplasia 7: 1058-1064.
Srivastava AN, Gupta A, Srivastava S, Natu SM, Mittal B, Negi MP, Prasad R. 2010. Cisplatin combination chemotherapy induces oxidative stress in advance non small cell lung cancer patients. Asian Pac J Cancer Prev 11: 465-471.
Stahlhut C, Slack FJ. 2015. Combinatorial Action of MicroRNAs let-7 and miR-34 Effectively Synergizes with Erlotinib to Suppress Non-small Cell Lung Cancer Cell Proliferation. Cell Cycle 14: 2171-2180.
Storz P. 2005. Reactive oxygen species in tumor progression. Front Biosci 10: 1881-1896.
Sun D, Xu D, Zhang B. 2006. Rac signaling in tumorigenesis and as target for anticancer drug development. Drug Resist Updat 9: 274-287.
Tai KY, Shieh YS, Lee CS, Shiah SG, Wu CW. 2008. Axl promotes cell invasion by inducing MMP-9 activity through activation of NF-kappaB and Brg-1. Oncogene 27: 4044-4055.
Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. 2007. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proceedings of the National Academy of Sciences of the United States of America 104: 15472-15477.
Tobar N, Caceres M, Santibanez JF, Smith PC, Martinez J. 2008. RAC1 activity and intracellular ROS modulate the migratory potential of MCF-7 cells through a NADPH oxidase and NFkappaB-dependent mechanism. Cancer Lett 267: 125-132.
Tochhawng L, Deng S, Pervaiz S, Yap CT. 2012. Redox regulation of cancer cell migration and invasion. Mitochondrion.
Toyokuni S, Okamoto K, Yodoi J, Hiai H. 1995. Persistent oxidative stress in cancer. FEBS Lett 358: 1-3.
Tsai LH, Chen PM, Cheng YW, Chen CY, Sheu GT, Wu TC, Lee H. 2014. LKB1 loss by alteration of the NKX2-1/p53 pathway promotes tumor malignancy and predicts poor survival and relapse in lung adenocarcinomas. Oncogene 33: 3851-3860.
Tsurutani J, Fukuoka J, Tsurutani H, Shih JH, Hewitt SM, Travis WD, Jen J, Dennis PA. 2006. Evaluation of two phosphorylation sites improves the prognostic significance of Akt activation in non-small-cell lung cancer tumors. J Clin Oncol 24: 306-314.
Vafa O, Wade M, Kern S, Beeche M, Pandita TK, Hampton GM, Wahl GM. 2002. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol Cell 9: 1031-1044.
Vajkoczy P, Knyazev P, Kunkel A, Capelle HH, Behrndt S, von Tengg-Kobligk H, Kiessling F, Eichelsbacher U, Essig M, Read TA, et al. 2006. Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proc Natl Acad Sci U S A 103: 5799-5804.
Valverde P. 2005. Effects of Gas6 and hydrogen peroxide in Axl ubiquitination and downregulation. Biochem Biophys Res Commun 333: 180-185.
Vogt M, Munding J, Gruner M, Liffers ST, Verdoodt B, Hauk J, Steinstraesser L, Tannapfel A, Hermeking H. 2011. Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Archiv : an international journal of pathology 458: 313-322.
Wang MJ, Lin S. 2009. A region within the 5′-untranslated region of hypoxia-inducible factor-1alpha mRNA mediates its turnover in lung adenocarcinoma cells. The Journal of biological chemistry 284: 36500-36510.
Wang X, McCullough KD, Franke TF, Holbrook NJ. 2000. Epidermal growth factor receptor-dependent Akt activation by oxidative stress enhances cell survival. J Biol Chem 275: 14624-14631.
Wang Y, Xia H, Zhuang Z, Miao L, Chen X, Cai H. 2014. Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer. Cell death & disease 5: e1227.
Webster RJ, Giles KM, Price KJ, Zhang PM, Mattick JS, Leedman PJ. 2009. Regulation of epidermal growth factor receptor signaling in human cancer cells by microRNA-7. The Journal of biological chemistry 284: 5731-5741.
Weinberg F, Chandel NS. 2009. Reactive oxygen species-dependent signaling regulates cancer. Cell Mol Life Sci 66: 3663-3673.
Weinberg F, Hamanaka R, Wheaton WW, Weinberg S, Joseph J, Lopez M, Kalyanaraman B, Mutlu GM, Budinger GR, Chandel NS. 2010. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci U S A 107: 8788-8793.
Whitmarsh AJ, Shore P, Sharrocks AD, Davis RJ. 1995. Integration of MAP kinase signal transduction pathways at the serum response element. Science 269: 403-407.
Wimmel A, Glitz D, Kraus A, Roeder J, Schuermann M. 2001. Axl receptor tyrosine kinase expression in human lung cancer cell lines correlates with cellular adhesion. Eur J Cancer 37: 2264-2274.
Wu CW, Li AF, Chi CW, Lai CH, Huang CL, Lo SS, Lui WY, Lin WC. 2002. Clinical significance of AXL kinase family in gastric cancer. Anticancer Res 22: 1071-1078.
Wu WS. 2006. The signaling mechanism of ROS in tumor progression. Cancer Metastasis Rev 25: 695-705.
Wu X, Liu X, Koul S, Lee CY, Zhang Z, Halmos B. 2014. AXL kinase as a novel target for cancer therapy. Oncotarget 5: 9546-9563.
Wu YM, Robinson DR, Kung HJ. 2004. Signal pathways in up-regulation of chemokines by tyrosine kinase MER/NYK in prostate cancer cells. Cancer research 64: 7311-7320.
Xia C, Meng Q, Liu LZ, Rojanasakul Y, Wang XR, Jiang BH. 2007. Reactive oxygen species regulate angiogenesis and tumor growth through vascular endothelial growth factor. Cancer Res 67: 10823-10830.
Yamakuchi M, Ferlito M, Lowenstein CJ. 2008. miR-34a repression of SIRT1 regulates apoptosis. Proceedings of the National Academy of Sciences of the United States of America 105: 13421-13426.
Yan D, Zhou X, Chen X, Hu DN, Dong XD, Wang J, Lu F, Tu L, Qu J. 2009. MicroRNA-34a inhibits uveal melanoma cell proliferation and migration through downregulation of c-Met. Investigative ophthalmology & visual science 50: 1559-1565.
Yanagita M, Arai H, Nakano T, Ohashi K, Mizuno K, Fukatsu A, Doi T, Kita T. 2001. Gas6 induces mesangial cell proliferation via latent transcription factor STAT3. The Journal of biological chemistry 276: 42364-42369.
Younger ST, Corey DR. 2011. Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters. Nucleic acids research 39: 5682-5691.
Zhang JY, Zhang D, Wang EH. 2011. Overexpression of small GTPases directly correlates with expression of delta-catenin and their coexpression predicts a poor clinical outcome in nonsmall cell lung cancer. Mol Carcinog.
Zhang Z, Lee JC, Lin L, Olivas V, Au V, LaFramboise T, Abdel-Rahman M, Wang X, Levine AD, Rho JK, et al. 2012. Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer. Nature genetics 44: 852-860.
Zhao J, Kelnar K, Bader AG. 2014. In-depth analysis shows synergy between erlotinib and miR-34a. PloS one 9: e89105.
Zieba M, Suwalski M, Kwiatkowska S, Piasecka G, Grzelewska-Rzymowska I, Stolarek R, Nowak D. 2000. Comparison of hydrogen peroxide generation and the content of lipid peroxidation products in lung cancer tissue and pulmonary parenchyma. Respir Med 94: 800-805.
指導教授 莊雙恩、陳盛良(Shung-En Chuang Shen-Liang Chen) 審核日期 2016-1-21
推文 facebook   plurk   twitter   funp   google   live   udn   HD   myshare   reddit   netvibes   friend   youpush   delicious   baidu   
網路書籤 Google bookmarks   del.icio.us   hemidemi   myshare   

若有論文相關問題,請聯絡國立中央大學圖書館推廣服務組 TEL:(03)422-7151轉57407,或E-mail聯絡  - 隱私權政策聲明