Swelling-induced upregulation of miR-141-3p inhibits hepatocyte proliferation.
Camsap1, calmodulin-regulated spectrin-associated protein 1
Cdc25a, cell division cycle 25A
Cdk8, cyclin dependent kinase 8
Colchicine
Cpt2, carnitine palmitoyl transferase 2
Dmxl1, Dmx Like 1
Dstyk, dual serine/threonine and tyrosine protein kinase
Duoxa2, dual oxidase maturation factor 2
ECM, extracellular matrix
Eml4, EMAP like 4
GO, gene ontology
Gucy2c, guanylate cyclase 2C
Hepatocytes
Hypoosmolarity
Liver perfusion
Liver regeneration
Luc7l3, LUC7 like 3 pre-MRNA splicing factor
Msantd2, Myb/SANT DNA binding domain containing 2
Nags, N-acetyl glutamate synthase
Nfat5, nuclear factor of activated t cells 5
Osmosis
PHx
PHx, partial hepatectomy
PI, propidium iodide
Prmt1, protein arginine methyltransferase 1
RT, room temperature
Rab30, member RAS Oncogene Family
Rps6, ribosomal Protein S6
Scnn1a, sodium channel epithelial 1 subunit alpha
Slc39a10, solute carrier family 39 member 10
Tfeb, transcription factor EB
Timp1, tissue inhibitor of metalloproteinase 1
Zmpste24, zinc metallopeptidase STE24
miR-141-3p
miRNA, microRNA
microRNA
qPCR, quantitative PCR
Journal
JHEP reports : innovation in hepatology
ISSN: 2589-5559
Titre abrégé: JHEP Rep
Pays: Netherlands
ID NLM: 101761237
Informations de publication
Date de publication:
Apr 2022
Apr 2022
Historique:
received:
26
05
2021
revised:
19
12
2021
accepted:
23
12
2021
entrez:
15
3
2022
pubmed:
16
3
2022
medline:
16
3
2022
Statut:
epublish
Résumé
MicroRNAs (miRNAs) act as a regulatory mechanism on a post-transcriptional level by repressing gene transcription/translation and play a central role in the cellular stress response. Osmotic changes occur in a variety of diseases including liver cirrhosis and hepatic encephalopathy. Changes in cell hydration and alterations of the cellular volume are major regulators of cell function and gene expression. In this study, the modulation of hepatic gene expression in response to hypoosmolarity was studied. mRNA analyses of normo- and hypoosmotic perfused rat livers by gene expression arrays were used to identify miRNA and their potential target genes associated with cell swelling preceding cell proliferation. Selected miR-141-3p was also investigated in isolated hepatocytes treated with miRNA mimic, cell stretching, and after partial hepatectomy. Inhibitor perfusion studies were performed to unravel signalling pathways responsible for miRNA upregulation. Using genome-wide transcriptomic analysis, it was shown that hypoosmotic exposure led to differential gene expression in perfused rat liver. Moreover, miR-141-3p was upregulated by hypoosmolarity in perfused rat liver and in primary hepatocytes. In concert with this, miR-141-3p upregulation was prevented after Src-, Erk-, and p38-MAPK inhibition. Furthermore, luciferase reporter assays demonstrated that miR-141-3p targets cyclin dependent kinase 8 ( Src-mediated upregulation of miR-141-3p was found in hepatocytes in response to hypoosmotic swelling and mechanical stretching. Because of its antiproliferative function, miR-141-3p may counter-regulate the proliferative effects triggered by these stimuli. In this study, we identified microRNA 141-3p as an osmosensitive miRNA, which inhibits proliferation during liver cell swelling. Upregulation of microRNA 141-3p, controlled by Src-, Erk-, and p38-MAPK signalling, results in decreased mRNA levels of various genes involved in metabolic processes, macromolecular biosynthesis, and cell cycle progression.
Sections du résumé
Background & Aims
UNASSIGNED
MicroRNAs (miRNAs) act as a regulatory mechanism on a post-transcriptional level by repressing gene transcription/translation and play a central role in the cellular stress response. Osmotic changes occur in a variety of diseases including liver cirrhosis and hepatic encephalopathy. Changes in cell hydration and alterations of the cellular volume are major regulators of cell function and gene expression. In this study, the modulation of hepatic gene expression in response to hypoosmolarity was studied.
Methods
UNASSIGNED
mRNA analyses of normo- and hypoosmotic perfused rat livers by gene expression arrays were used to identify miRNA and their potential target genes associated with cell swelling preceding cell proliferation. Selected miR-141-3p was also investigated in isolated hepatocytes treated with miRNA mimic, cell stretching, and after partial hepatectomy. Inhibitor perfusion studies were performed to unravel signalling pathways responsible for miRNA upregulation.
Results
UNASSIGNED
Using genome-wide transcriptomic analysis, it was shown that hypoosmotic exposure led to differential gene expression in perfused rat liver. Moreover, miR-141-3p was upregulated by hypoosmolarity in perfused rat liver and in primary hepatocytes. In concert with this, miR-141-3p upregulation was prevented after Src-, Erk-, and p38-MAPK inhibition. Furthermore, luciferase reporter assays demonstrated that miR-141-3p targets cyclin dependent kinase 8 (
Conclusions
UNASSIGNED
Src-mediated upregulation of miR-141-3p was found in hepatocytes in response to hypoosmotic swelling and mechanical stretching. Because of its antiproliferative function, miR-141-3p may counter-regulate the proliferative effects triggered by these stimuli.
Lay summary
UNASSIGNED
In this study, we identified microRNA 141-3p as an osmosensitive miRNA, which inhibits proliferation during liver cell swelling. Upregulation of microRNA 141-3p, controlled by Src-, Erk-, and p38-MAPK signalling, results in decreased mRNA levels of various genes involved in metabolic processes, macromolecular biosynthesis, and cell cycle progression.
Identifiants
pubmed: 35287291
doi: 10.1016/j.jhepr.2022.100440
pii: S2589-5559(22)00012-X
pmc: PMC8917307
doi:
Types de publication
Journal Article
Langues
eng
Pagination
100440Informations de copyright
© 2022 The Author(s).
Déclaration de conflit d'intérêts
The authors have declared no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details.
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