miR-125b Upregulates miR-34a and Sequentially Activates Stress Adaption and Cell Death Mechanisms in Multiple Myeloma.
apoptosis
autophagy
miR-125b
miR-34a
miRNA therapeutics
miRNome
multiple myeloma
next generation sequencing
senescence
signal transduction
Journal
Molecular therapy. Nucleic acids
ISSN: 2162-2531
Titre abrégé: Mol Ther Nucleic Acids
Pays: United States
ID NLM: 101581621
Informations de publication
Date de publication:
07 Jun 2019
07 Jun 2019
Historique:
received:
21
09
2018
revised:
26
02
2019
accepted:
26
02
2019
pubmed:
23
4
2019
medline:
23
4
2019
entrez:
23
4
2019
Statut:
ppublish
Résumé
miR-125b, ubiquitously expressed and frequently dysregulated in several tumors, has gained special interest in the field of cancer research, displaying either oncogenic or oncosuppressor potential based on tumor type. We have previously demonstrated its tumor-suppressive role in multiple myeloma (MM), but the analysis of molecular mechanisms needs additional investigation. The purpose of this study was to explore the effects of miR-125b and its chemically modified analogs in modulating cell viability and cancer-associated molecular pathways, also focusing on the functional aspects of stress adaptation (autophagy and senescence), as well as programmed cell death (apoptosis). Based on the well-known low microRNA (miRNA) stability in therapeutic application, we designed chemically modified miR-125b mimics, laying the bases for their subsequent investigation in in vivo models. Our study clearly confirmed an oncosuppressive function depending on the repression of multiple targets, and it allowed the identification, for the first time, of miR-125b-dependent miR-34a stimulation as a possible consequence of the inhibitory role on the interleukin-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3)/miR-34a feedback loop. Moreover, we identified a pattern of miR-125b-co-regulated miRNAs, shedding light on possible new players of anti-MM activity. Finally, functional studies also revealed a sequential activation of senescence, autophagy, and apoptosis, thus indicating, for the first two processes, an early cytoprotective and inhibitory role from apoptosis activation.
Identifiants
pubmed: 31009917
pii: S2162-2531(19)30054-X
doi: 10.1016/j.omtn.2019.02.023
pmc: PMC6479071
pii:
doi:
Types de publication
Journal Article
Langues
eng
Pagination
391-406Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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