Weissman Ran, Diamond Eli L, Haroche Julien, Pillar Nir, Shapira Guy, Durham Benjamin H, Buthorn Justin, Cohen Fleur, Ki Michelle, Stemer Galia, Ulaner Gary A, Amoura Zahir, Emile Jean-François, Mazor Roei D, Shomron Noam, Abdel-Wahab Omar I, Shpilberg Ofer, Hershkovitz-Rokah Oshrat
Department of Molecular Biology, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel.
Translational Research Lab, Assuta Medical Centers, Tel-Aviv 6971028, Israel.
Cancers (Basel). 2020 Nov 3;12(11):3240. doi: 10.3390/cancers12113240.
The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.
组织细胞肿瘤的发病机制由激活MAPK/ERK通路的突变驱动，但对于这些肿瘤中涉及的转录和转录后改变知之甚少。我们分析了厄尔德海姆-切斯特病（ECD）和朗格汉斯细胞组织细胞增多症（LCH）患者血浆样本和组织活检中的微小RNA（miRNA）表达。与健康对照（HC）相比，计算机分析揭示了miRNA在调节这些肿瘤基因表达中的潜在作用。NanoString分析显示，与11名HC相比，16名ECD患者中有101种血浆miRNA差异表达，其中95%下调。通过qRT-PCR在32名ECD患者、7名LCH患者和15名HC的扩大队列中进一步评估了miRNA-15a-5p、-15b-5p、-21-5p、-107、-221-3p、-320e、-630和let-7家族miRNA。与ECD相比，6种miRNA（let-7a、let-7c、miR-15a-5p、miR-15b-5p、miR-107和miR-630）在LCH血浆和组织样本中高表达。通路富集分析表明miRNA对炎症和促生存信号通路有贡献。此外，与HC相比，未经治疗的ECD患者中let-7家族成员下调，而用MAPK/ERK信号抑制剂治疗16周导致其上调，这与PET-CT所见的放射学反应平行。该研究突出了miRNA对ECD和LCH的炎症和肿瘤特征的潜在贡献。
