A Study on the mechanism of AXL-mediated cell migration and survival in non-small cell lung cancer
| Autor: | Chun-Yu Cho, 卓俊宇 |
|---|---|
| Rok vydání: | 2016 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 104 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. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
| Externí odkaz: |
|