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Distinct microRNA Signature and Suppression of ZFP36L1 Define ASCL1-Positive Lung Adenocarcinoma

Enokido, Takayoshi ; Horie, Masafumi ; Yoshino, Seiko ; Suzuki, Hiroshi I. ; Matsuki, Rei ; Brunnstrom, Hans LU orcid ; Micke, Patrick ; Nagase, Takahide ; Saito, Akira and Miyashita, Naoya (2024) In Molecular Cancer Research 22(1). p.29-40
Abstract

Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas (LUAD) and exerts tumor-promoting effects. Here, we explored miRNA profiles in ASCL1-positive LUADs and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95–3p/miR-95–5p, miR-124–3p, and members of the miR-17~92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive LUADs. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates... (More)

Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas (LUAD) and exerts tumor-promoting effects. Here, we explored miRNA profiles in ASCL1-positive LUADs and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95–3p/miR-95–5p, miR-124–3p, and members of the miR-17~92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive LUADs. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124–3p and members of the miR-17~92 family. Integrative transcriptomic analyses identified ZFP36 ring finger protein like 1 (ZFP36L1) as a target gene of miR-124–3p, and IHC studies demonstrated that ASCL1-positive LUADs are associated with low ZFP36L1 protein levels. Cell culture studies showed that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell-cycle progression. Moreover, ZFP36L1 negatively regulated several genes including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1). In conclusion, our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124–3p could modulate gene expression, providing evidence that ASCL1-mediated regulation of miRNAs shapes molecular features of ASCL1-positive LUADs.

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; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cancer Research
volume
22
issue
1
pages
12 pages
publisher
American Association for Cancer Research
external identifiers
  • scopus:85181583176
  • pmid:37801008
ISSN
1541-7786
DOI
10.1158/1541-7786.MCR-23-0229
language
English
LU publication?
yes
id
656a624a-7f1e-471b-8198-b8cad8b9f83f
date added to LUP
2024-02-07 11:55:56
date last changed
2025-04-24 05:45:15
@article{656a624a-7f1e-471b-8198-b8cad8b9f83f,
  abstract     = {{<p>Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas (LUAD) and exerts tumor-promoting effects. Here, we explored miRNA profiles in ASCL1-positive LUADs and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95–3p/miR-95–5p, miR-124–3p, and members of the miR-17~92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive LUADs. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124–3p and members of the miR-17~92 family. Integrative transcriptomic analyses identified ZFP36 ring finger protein like 1 (ZFP36L1) as a target gene of miR-124–3p, and IHC studies demonstrated that ASCL1-positive LUADs are associated with low ZFP36L1 protein levels. Cell culture studies showed that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell-cycle progression. Moreover, ZFP36L1 negatively regulated several genes including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1). In conclusion, our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124–3p could modulate gene expression, providing evidence that ASCL1-mediated regulation of miRNAs shapes molecular features of ASCL1-positive LUADs.</p>}},
  author       = {{Enokido, Takayoshi and Horie, Masafumi and Yoshino, Seiko and Suzuki, Hiroshi I. and Matsuki, Rei and Brunnstrom, Hans and Micke, Patrick and Nagase, Takahide and Saito, Akira and Miyashita, Naoya}},
  issn         = {{1541-7786}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{29--40}},
  publisher    = {{American Association for Cancer Research}},
  series       = {{Molecular Cancer Research}},
  title        = {{Distinct microRNA Signature and Suppression of ZFP36L1 Define ASCL1-Positive Lung Adenocarcinoma}},
  url          = {{http://dx.doi.org/10.1158/1541-7786.MCR-23-0229}},
  doi          = {{10.1158/1541-7786.MCR-23-0229}},
  volume       = {{22}},
  year         = {{2024}},
}