Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells

• Published in: RNA (Cambridge) Vol. 22; no. 2; pp. 303 - 315
• Main Authors: Cho, Chun-Yu, Huang, Jhy-Shrian, Shiah, Shine-Gwo, Chung, Shih-Ying, Lay, Jong-Ding, Yang, Ya-Yu, Lai, Gi-Ming, Cheng, Ann-Lii, Chen, Li-Tzong, Chuang, Shuang-En
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.02.2016
• Subjects: Apoptosis; Binding Sites; Cell Line, Tumor; Epithelial Cells - metabolism; Epithelial Cells - pathology; ets-Domain Protein Elk-1 - genetics; ets-Domain Protein Elk-1 - metabolism; Feedback, Physiological; Gene Expression Regulation, Neoplastic; Humans; Lung - metabolism; Lung - pathology; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; Microarray Analysis; MicroRNAs - genetics; MicroRNAs - metabolism; Phosphorylation; Protein Binding; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Signal Transduction; Tyrosine - metabolism; apoptosis; AXL; miR-34a; ELK1; JNK; feedback loop regulation
• ISSN: 1355-8382; 1469-9001
• DOI: 10.1261/rna.052571.115

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.