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

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卓俊宇(Chun-Yu Cho) 查詢紙本館藏

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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)

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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

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指導教授

莊雙恩、陳盛良(Shung-En Chuang Shen-Liang Chen)

審核日期

2016-1-21

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