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

   


Authors: Weissman, R.; Diamond, E. L.; Haroche, J.; Durham, B. H.; Cohen, F.; Buthorn, J.; Amoura, Z.; Emile, J. F.; Mazor, R. D.; Shomron, N.; Abdel-Wahab, O. I.; Shpilberg, O.; Hershkovitz-Rokah, O.
Article Title: 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. © 2021, The Author(s).
Keywords: immunohistochemistry; signal transduction; mitogen activated protein kinase; clinical article; controlled study; protein expression; unclassified drug; gene mutation; human cell; genetics; pathogenesis; treatment duration; metabolism; gene; gene overexpression; protein bcl 2; apoptosis; enzyme inhibition; microrna; gene expression; cell growth; down-regulation; cohort analysis; gene function; protein bcl xl; enzyme linked immunosorbent assay; tumor suppressor gene; genetic transfection; western blotting; gene control; ras protein; down regulation; real time polymerase chain reaction; upregulation; up-regulation; micrornas; gamma interferon inducible protein 10; cell cycle regulation; b raf kinase; genes, tumor suppressor; rna extraction; microrna let 7; vemurafenib; chemokine cxcl10; lin28a gene; humans; human; article; erdheim chester disease; luciferase assay; erdheim-chester disease; cobimetinib; cell proliferation assay; ba/f3 cell line; oci-aml-3 cell line; microrna 15a 5p; cxcl10 protein, human; b-lymphocyte cell line; kg 1a cell line
Journal Title: Leukemia
Volume: 36
Issue: 4
ISSN: 0887-6924
Publisher: Nature Publishing Group  
Date Published: 2022-04-01
Start Page: 1139
End Page: 1149
Language: English
DOI: 10.1038/s41375-021-01472-2
PUBMED: 34785791
PROVIDER: scopus
PMCID: PMC8979810
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85119381268&doi=10.1038%2fs41375-021-01472-2&partnerID=40&md5=b708b48a43003609ed757c4782c12859
Notes: Article -- Export Date: 25 April 2022 -- Source: Scopus
Altmetric
What is Altmetric?
Citation Impact
What is Dimensions Citation Badge?
BMJ Impact Analytics
MSK Authors
  1. Omar Ibrahim Abdel-Wahab
    573 Abdel-Wahab
  2. Eli Louis Diamond
    203 Diamond
  3. Benjamin Heath Durham
    115 Durham
  4. Justin J Buthorn
    22 Buthorn
Related MSK Work