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

doi:10.1261/rna.052571.115

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 journal › Article › peer-review

27 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 language	English
Pages (from-to)	303-315
Number of pages	13
Journal	RNA
Volume	22
Issue number	2
DOIs	https://doi.org/10.1261/rna.052571.115
Publication status	Published - Feb 2016

Keywords

AXL
Apoptosis
ELK1
Feedback loop regulation
JNK
MiR-34a

ASJC Scopus subject areas

Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1261/rna.052571.115

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@article{36797f1c514148a491f4dd024d681f96,

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 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.",

keywords = "AXL, Apoptosis, ELK1, Feedback loop regulation, JNK, MiR-34a",

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

note = "Funding Information: This work was supported by the National Health Research Institutes (CA-104-PP-14, CA-104-SP-01), the Ministry of Health and Welfare (MOHW104-TDU-B-212-124-008), and the Ministry of Science and Technology (MOST-103-2320-B-400-009, NSC 99- 2314-B-400-001-MY3), Taiwan. We thank Rigel Pharmaceuticals (South San Francisco, CA) for providing the AXL inhibitor R428. We are also grateful to Dr. Shen-Liang Chen (National Central University, Taiwan) for help during the revision. Publisher Copyright: {\textcopyright} 2016 Cho et al.",

year = "2016",

month = feb,

doi = "10.1261/rna.052571.115",

language = "English",

volume = "22",

pages = "303--315",

journal = "RNA",

issn = "1355-8382",

publisher = "Cold Spring Harbor Laboratory Press",

number = "2",

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TY - JOUR

T1 - Negative feedback regulation of AXL by miR-34a modulates apoptosis in lung cancer cells

AU - Cho, Chun Yu

AU - Huang, Jhy Shrian

AU - Shiah, Shine Gwo

AU - Chung, Shih Ying

AU - Lay, Jong Ding

AU - Yang, Ya Yu

AU - Lai, Gi Ming

AU - Cheng, Ann Lii

AU - Chen, Li Tzong

AU - Chuang, Shuang En

N1 - Funding Information: This work was supported by the National Health Research Institutes (CA-104-PP-14, CA-104-SP-01), the Ministry of Health and Welfare (MOHW104-TDU-B-212-124-008), and the Ministry of Science and Technology (MOST-103-2320-B-400-009, NSC 99- 2314-B-400-001-MY3), Taiwan. We thank Rigel Pharmaceuticals (South San Francisco, CA) for providing the AXL inhibitor R428. We are also grateful to Dr. Shen-Liang Chen (National Central University, Taiwan) for help during the revision. Publisher Copyright: © 2016 Cho et al.

PY - 2016/2

Y1 - 2016/2

N2 - 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.

AB - 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.

KW - AXL

KW - Apoptosis

KW - ELK1

KW - Feedback loop regulation

KW - JNK

KW - MiR-34a

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JO - RNA

JF - RNA

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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