Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells
- Chun-Yu Cho1,2,9,
- Jhy-Shrian Huang1,3,4,5,9,
- Shine-Gwo Shiah1,
- Shih-Ying Chung1,
- Jong-Ding Lay6,
- Ya-Yu Yang1,
- Gi-Ming Lai1,3,7,
- Ann-Lii Cheng1,8,
- Li-Tzong Chen1 and
- Shuang-En Chuang1,2
- 1National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan
- 2Department of Life Sciences, National Central University, Taoyuan 32001, Taiwan
- 3Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
- 4Health Examination Center, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan
- 5School of Medicine, College of Medicine, I-Shou University, Kaohsiung 84001, Taiwan
- 6Department of Nursing, National Taichung University of Science and Technology, Taichung 40401, Taiwan
- 7Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
- 8Departments of Internal Medicine and Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan
- Corresponding author: sechuang{at}nhri.org.tw
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↵9 These authors contributed equally to this work.
Abstract
The AXL receptor tyrosine kinase is frequently overexpressed in cancers and is important in cancer invasion/metastasis and chemoresistance. Here, we demonstrate a regulatory feedback loop between AXL and microRNA (miRNA) at the post-transcriptional level. Both the GAS6-binding domain and the kinase domain of AXL, particularly the Y779 tyrosine phosphorylation site, are shown to be crucial for this autoregulation. To clarify the role of miRNAs in this regulation loop, approaches using bioinformatics and molecular techniques were applied, revealing that miR-34a may target the 3′ UTR of AXL mRNA to inhibit AXL expression. Interestingly and importantly, AXL overexpression may induce miR-34a expression by activating the transcription factor ELK1 via the JNK signaling pathway. In addition, ectopic overexpression of ELK1 promotes apoptosis through, in part, down-regulation of AXL. Therefore, we propose that AXL is autoregulated by miR-34a in a feedback loop; this may provide a novel opportunity for developing AXL-targeted anticancer therapies.
Keywords
Footnotes
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Abbreviations: RTK, receptor tyrosine kinase; miRNA, microRNA; UTR, untranslated region; EMT, epithelial–mesenchymal transition; JNK, c-Jun amino-terminal kinases; ELK1, ETS-Like Gene 1; Gas6, growth arrest-specific 6; PI3K, phosphoinositide 3-kinase; PARP, poly-ADP-ribose polymerase
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Article published online ahead of print. Article and publication date are at http://www.rnajournal.org/cgi/doi/10.1261/rna.052571.115.
- Received June 4, 2015.
- Accepted November 18, 2015.
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