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

Abstract

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 BRAFV600E 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.

Immunogenic cell death mediated TLR3/4-activated MSCs in U87 GBM cell line

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COVID-19 Vaccination in Pregnancy: Pilot Study for Maternal and Neonatal MicroRNA Profiles

“…Furthermore, miR-15a-5p might be involved in the inflammatory cascade during sepsis, potentially via the activation of the NF-κB pathway and targeting TNIP2 [ 56 ]. Overexpression of miR-15a-5p has been shown to inhibit cell growth and induce tumor cell apoptosis, primarily through the downregulation of Bcl-2 and Bcl-xl [ 57 ].…”

Mutant PIK3CA is a targetable driver alteration in histiocytic neoplasms

“…MiRNA was reverse-transcribed with miRNA-specific stem-looped RT primers (Life Technologies, ThermoFisher Scientific Inc) and detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) as previously described. 20 …”

“…Reaction conditions for the gene expression assays were similar to the miRNA qRT-PCR described before. 20 …”