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: | |
Notes: | Article -- Export Date: 25 April 2022 -- Source: Scopus |