MicroRNA-15a-5p acts as a tumor suppressor in histiocytosis by mediating CXCL10-ERK-LIN28a-let-7 axis

Erdheim-Chester disease (ECD) is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. ECD patients harbor recurrent mutations of genes associated with the RAS/RAF/MEK/ERK signaling pathway, particularly, the BRAF mutation. Following our previous f...

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Bibliographic Details
Published in:Leukemia 2022-04, Vol.36 (4), p.1139-1149
Main Authors: Weissman, Ran, Diamond, Eli L, Haroche, Julien, Durham, Benjamin H, Cohen, Fleur, Buthorn, Justin, Amoura, Zahir, Emile, Jean-François, Mazor, Roei D, Shomron, Noam, Abdel-Wahab, Omar I, Shpilberg, Ofer, Hershkovitz-Rokah, Oshrat
Format: Article
Language:English
Subjects:
Apoptosis
Bcl-2 protein
Bcl-x protein
Bioinformatics
Chemokine CXCL10 - genetics
Chemokine CXCL10 - metabolism
Chemokines
Chromosome 5
CXCL10 protein
Down-Regulation
Erdheim-Chester Disease
Extracellular signal-regulated kinase
Gene regulation
Genes, Tumor Suppressor
Histiocytosis
Humans
Life Sciences
MAP kinase
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
Mutation
Organs
Pathogenesis
Post-transcription
Raf protein
Ribonucleic acid
RNA
Signal transduction
Signaling
Tumor suppressor genes
Tumors
Up-Regulation
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Summary:Erdheim-Chester disease (ECD) is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. ECD patients harbor recurrent mutations of genes associated with the RAS/RAF/MEK/ERK signaling pathway, particularly, the BRAF mutation. Following our previous finding that miR-15a-5p is the most prominently downregulated microRNA in ECD patients compared to healthy individuals, we elucidated its role in ECD pathogenesis. Bioinformatics analysis followed by a luciferase assay showed that chemokine ligand 10 (CXCL10) is a target gene regulated by miRNA-15a-5p. This was confirmed in 24/34 ECD patients that had low expression of miR-15a-5p concurrent with upregulated CXCL10. Overexpression of miR-15a-5p in cell lines harboring BRAF or RAS mutations (Ba/F3, KG-1a and OCI-AML3) resulted in CXCL10 downregulation, followed by LIN28a and p-ERK signaling downregulation and let-7 family upregulation. Overexpression of miR-15a-5p inhibited cell growth and induced apoptosis by decreasing Bcl-2 and Bcl-xl levels. Analysis of sequential samples from 7 ECD patients treated with MAPK inhibitors (vemurafenib/cobimetinib) for 4 months showed miR-15a-5p upregulation and CXCL10 downregulation. Our findings suggest that miR-15a-5p is a tumor suppressor in ECD through the CXCL10-ERK-LIN28a-let7 axis, highlighting another layer of post-transcriptional regulation in this disease. Upregulation of miR-15a-5p in ECD patients may have a potential therapeutic role.
ISSN:0887-6924
1476-5551
1476-5551
DOI:10.1038/s41375-021-01472-2