Department of Biomedical Sciences and Human Oncology, Unit of General Pathology, University of Bari Aldo Moro Medical School, Bari, Italy.
Department of Biomedical Sciences and Human Oncology, Unit of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro Medical School, Bari, Italy.
J Pathol. 2019 Feb;247(2):241-253. doi: 10.1002/path.5187.
Aberrant microRNA (miR) expression has an important role in tumour progression, but its involvement in bone marrow fibroblasts of multiple myeloma patients remains undefined. We demonstrate that a specific miR profile in bone marrow fibroblasts parallels the transition from monoclonal gammopathy of undetermined significance (MGUS) to myeloma. Overexpression of miR-27b-3p and miR-214-3p triggers proliferation and apoptosis resistance in myeloma fibroblasts via the FBXW7 and PTEN/AKT/GSK3 pathways, respectively. Transient transfection of miR-27b-3p and miR-214-3p inhibitors demonstrates a cooperation between these two miRNAs in the expression of the anti-apoptotic factor MCL1, suggesting that miR-27b-3p and miR-214-3p negatively regulate myeloma fibroblast apoptosis. Furthermore, myeloma cells modulate miR-27b-3p and miR-214-3p expression in fibroblasts through the release of exosomes. Indeed, tumour cell-derived exosomes induce an overexpression of both miRNAs in MGUS fibroblasts not through a simple transfer mechanism but by de novo synthesis triggered by the transfer of exosomal WWC2 protein that regulates the Hippo pathway. Increased levels of miR-27b-3p and miR-214-3p in MGUS fibroblasts co-cultured with myeloma cell-derived exosomes enhance the expression of fibroblast activation markers αSMA and FAP. These data show that the MGUS-to-myeloma transition entails an aberrant miRNA profile in marrow fibroblasts and highlight a key role of myeloma cells in modifying the bone marrow microenvironment by reprogramming the marrow fibroblasts' behaviour. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
异常的 microRNA（miR）表达在肿瘤进展中具有重要作用，但它在多发性骨髓瘤患者骨髓成纤维细胞中的作用仍未确定。我们证明，骨髓成纤维细胞中的特定 miR 谱与从意义未明的单克隆丙种球蛋白血症（MGUS）向骨髓瘤的转变平行。miR-27b-3p 和 miR-214-3p 的过表达分别通过 FBXW7 和 PTEN/AKT/GSK3 通路触发骨髓瘤成纤维细胞的增殖和抗凋亡抵抗。瞬时转染 miR-27b-3p 和 miR-214-3p 抑制剂表明这两种 miRNA 在抗凋亡因子 MCL1 的表达中具有协同作用，表明 miR-27b-3p 和 miR-214-3p 负调控骨髓瘤成纤维细胞凋亡。此外，骨髓瘤细胞通过释放外泌体调节成纤维细胞中 miR-27b-3p 和 miR-214-3p 的表达。事实上，肿瘤细胞衍生的外泌体通过 Hippo 通路调节蛋白 WWC2 的转移触发从头合成，而不是通过简单的转移机制，诱导 MGUS 成纤维细胞中这两种 miRNA 的过度表达。与骨髓瘤细胞衍生的外泌体共培养的 MGUS 成纤维细胞中 miR-27b-3p 和 miR-214-3p 的水平升高会增强成纤维细胞活化标记物 αSMA 和 FAP 的表达。这些数据表明，MGUS 向骨髓瘤的转变涉及骨髓成纤维细胞中异常的 miRNA 谱，并强调骨髓瘤细胞通过重塑骨髓成纤维细胞的行为改变骨髓微环境的关键作用。版权所有©2018 英国和爱尔兰病理学会。由 John Wiley & Sons，Ltd 出版。
