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

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712679/
https://www.ncbi.nlm.nih.gov/pubmed/26667302
http://dx.doi.org/10.1261/rna.052571.115
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author 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
author_facet 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
author_sort Cho, Chun-Yu
collection PubMed
description 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.
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spelling pubmed-47126792017-02-01 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 RNA Article 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. Cold Spring Harbor Laboratory Press 2016-02 /pmc/articles/PMC4712679/ /pubmed/26667302 http://dx.doi.org/10.1261/rna.052571.115 Text en © 2016 Cho et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Article
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
title Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells
title_full Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells
title_fullStr Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells
title_full_unstemmed Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells
title_short Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells
title_sort negative feedback regulation of axl by mir-34a modulates apoptosis in lung cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712679/
https://www.ncbi.nlm.nih.gov/pubmed/26667302
http://dx.doi.org/10.1261/rna.052571.115
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