title: Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells.
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.
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan Department of Life Sciences, National Central University, Taoyuan 32001, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Cho
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan Health Examination Center, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan School of Medicine, College of Medicine, I-Shou University, Kaohsiung 84001, Taiwan.
authors.forename: Jhy-Shrian
authors.initials: JS
authors.lastname: Huang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Shine-Gwo
authors.initials: SG
authors.lastname: Shiah
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Shih-Ying
authors.initials: SY
authors.lastname: Chung
authors.affiliation: Department of Nursing, National Taichung University of Science and Technology, Taichung 40401, Taiwan.
authors.forename: Jong-Ding
authors.initials: JD
authors.lastname: Lay
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Ya-Yu
authors.initials: YY
authors.lastname: Yang
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan Comprehensive Cancer Center, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Gi-Ming
authors.initials: GM
authors.lastname: Lai
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan Departments of Internal Medicine and Oncology, National Taiwan University Hospital, Taipei 10002, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan.
authors.forename: Li-Tzong
authors.initials: LT
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institutes, Miaoli 35053, Taiwan Department of Life Sciences, National Central University, Taoyuan 32001, Taiwan.
authors.forename: Shuang-En
authors.initials: SE
authors.lastname: Chuang
mesh_terms: D017209:Apoptosis; D001665:Binding Sites; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D046228:Microarray Analysis; D010766:Phosphorylation; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D050807:ets-Domain Protein Elk-1 / Q000235:genetics / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: C494112:ELK1 protein, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D050807:ets-Domain Protein Elk-1; D014443:Tyrosine; D020794:Receptor Protein-Tyrosine Kinases; D048670:MAP Kinase Kinase 4; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human
keywords: AXL; ELK1; JNK; apoptosis; feedback loop regulation; miR-34a