miR-21 antagonism abrogates Th17 tumor promoting functions in multiple myeloma.
Animals
Apoptosis
Biomarkers, Tumor
/ genetics
Bone Neoplasms
/ genetics
Case-Control Studies
Cell Proliferation
Gene Expression Regulation, Neoplastic
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
MicroRNAs
/ genetics
Multiple Myeloma
/ genetics
Prognosis
T-Lymphocytes, Regulatory
/ immunology
Th17 Cells
/ immunology
Tumor Cells, Cultured
Tumor Microenvironment
Xenograft Model Antitumor Assays
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
13
01
2020
accepted:
23
06
2020
revised:
21
06
2020
pubmed:
8
7
2020
medline:
23
3
2021
entrez:
8
7
2020
Statut:
ppublish
Résumé
Multiple myeloma (MM) is tightly dependent on inflammatory bone marrow microenvironment. IL-17 producing CD4+ T cells (Th17) sustain MM cells growth and osteoclasts-dependent bone damage. In turn, Th17 differentiation relies on inflammatory stimuli. Here, we investigated the role of miR-21 in Th17-mediated MM tumor growth and bone disease. We found that early inhibition of miR-21 in naive T cells (miR-21i-T cells) impaired Th17 differentiation in vitro and abrogated Th17-mediated MM cell proliferation and osteoclasts activity. We validated these findings in NOD/SCID-g-NULL mice, intratibially injected with miR-21i-T cells and MM cells. A Pairwise RNAseq and proteome/phosphoproteome analysis in Th17 cells demonstrated that miR-21 inhibition led to upregulation of STAT-1/-5a-5b, STAT-3 impairment and redirection of Th17 to Th1/Th2 like activated/polarized cells. Our findings disclose the role of miR-21 in pathogenic Th17 activity and open the avenue to the design of miR-21-targeting strategies to counteract microenvironment dependence of MM growth and bone disease.
Identifiants
pubmed: 32632096
doi: 10.1038/s41375-020-0947-1
pii: 10.1038/s41375-020-0947-1
doi:
Substances chimiques
Biomarkers, Tumor
0
MIRN21 microRNA, human
0
MicroRNAs
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
823-834Références
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