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

Chun Yu Cho, Jhy Shrian Huang, Shine Gwo Shiah, Shih Ying Chung, Jong Ding Lay, Ya Yu Yang, Gi Ming Lai, Ann Lii Cheng, Li Tzong Chen, Shuang En Chuang

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 posttranscriptional 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.

Original languageEnglish
Pages (from-to)303-315
Number of pages13
JournalRNA
Volume22
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

Fingerprint

MicroRNAs
Lung Neoplasms
Activating Transcription Factors
Apoptosis
MAP Kinase Signaling System
Receptor Protein-Tyrosine Kinases
3' Untranslated Regions
Computational Biology
Tyrosine
Neoplasms
Homeostasis
Phosphotransferases
Down-Regulation
Phosphorylation
Neoplasm Metastasis
Messenger RNA
Therapeutics

Keywords

  • Apoptosis
  • AXL
  • ELK1
  • Feedback loop regulation
  • JNK
  • MiR-34a

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Cho, C. Y., Huang, J. S., Shiah, S. G., Chung, S. Y., Lay, J. D., Yang, Y. Y., ... Chuang, S. E. (2016). Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells. RNA, 22(2), 303-315. https://doi.org/10.1261/rna.052571.115

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

In: RNA, Vol. 22, No. 2, 01.02.2016, p. 303-315.

Research output: Contribution to journalArticle

Cho, CY, Huang, JS, Shiah, SG, Chung, SY, Lay, JD, Yang, YY, Lai, GM, Cheng, AL, Chen, LT & Chuang, SE 2016, 'Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells', RNA, vol. 22, no. 2, pp. 303-315. https://doi.org/10.1261/rna.052571.115
Cho CY, Huang JS, Shiah SG, Chung SY, Lay JD, Yang YY et al. Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells. RNA. 2016 Feb 1;22(2):303-315. https://doi.org/10.1261/rna.052571.115
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. / Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells. In: RNA. 2016 ; Vol. 22, No. 2. pp. 303-315.
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