Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.
Department of Gastroenterology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China.
Cancer Res. 2020 May 15;80(10):2031-2044. doi: 10.1158/0008-5472.CAN-19-1077. Epub 2020 Mar 19.
Multiple myeloma is an incurable refractory hematologic malignancy arising from plasma cells in the bone marrow. Here we investigated miR-26a function in multiple myeloma and tested single-wall carbon nanotube delivery of miR-26a and . miR-26a was downregulated in patients with multiple myeloma cells compared with plasma cells from healthy donors. miR-26a overexpression inhibited proliferation and migration and induced apoptosis in multiple myeloma cell lines. To identify the targets of miR-26a, RPMI8226-V-miR-26-GFP and RPMI8226-V-GFP cells were cultured using stable isotope labeling by amino acids in cell culture (SILAC) medium, followed by mass spectrometry analysis. In multiple myeloma cells overexpressing miR-26a, CD38 protein was downregulated and subsequently confirmed to be a direct target of miR-26a. Depletion of CD38 in multiple myeloma cells duplicated the multiple myeloma inhibition observed with exogenous expression of miR-26a, whereas restoration of CD38 overcame the inhibition of miR-26a in multiple myeloma cells. In a human multiple myeloma xenograft mouse model, overexpression of miR-26a inhibited CD38 expression, provoked cell apoptosis, and inhibited cell proliferation. Daratumumab is the first CD38 antibody drug for monotherapy and combination therapy for patients with multiple myeloma, but eventually resistance develops. In multiple myeloma cells, CD38 remained at low level during daratumumab treatment, but a high-quality response is sustained. In daratumumab-resistant multiple myeloma cells, CD38 expression was completely restored but failed to correlate with daratumumab-induced cell death. Therefore, a therapeutic strategy to confer selection pressure to maintain low CD38 expression in multiple myeloma cells may have clinical benefit. SIGNIFICANCE: These results highlight the tumor suppressor function of miR-26a via its targeting of CD38 and suggest the therapeutic potential of miR-26a in patients with multiple myeloma.
多发性骨髓瘤是一种源自骨髓浆细胞的不可治愈的难治性血液恶性肿瘤。在这里，我们研究了 miR-26a 在多发性骨髓瘤中的功能，并测试了单壁碳纳米管递送 miR-26a 和 。与健康供体的浆细胞相比，多发性骨髓瘤患者的细胞中 miR-26a 表达下调。miR-26a 过表达抑制多发性骨髓瘤细胞系的增殖和迁移，并诱导细胞凋亡。为了鉴定 miR-26a 的靶标，使用稳定同位素标记通过细胞培养中的氨基酸（SILAC）培养基培养 RPMI8226-V-miR-26-GFP 和 RPMI8226-V-GFP 细胞，随后进行质谱分析。在过表达 miR-26a 的多发性骨髓瘤细胞中，CD38 蛋白下调，随后证实其为 miR-26a 的直接靶标。在多发性骨髓瘤细胞中耗尽 CD38 可复制外源性表达 miR-26a 观察到的多发性骨髓瘤抑制，而恢复 CD38 则克服了 miR-26a 在多发性骨髓瘤细胞中的抑制作用。在人多发性骨髓瘤异种移植小鼠模型中，miR-26a 的过表达抑制 CD38 表达，引发细胞凋亡并抑制细胞增殖。达雷妥尤单抗是第一个用于单药和联合治疗多发性骨髓瘤患者的 CD38 抗体药物，但最终会产生耐药性。在多发性骨髓瘤细胞中，达雷妥尤单抗治疗期间 CD38 仍保持低水平，但持续获得高质量反应。在达雷妥尤单抗耐药的多发性骨髓瘤细胞中，CD38 表达完全恢复，但与达雷妥尤单抗诱导的细胞死亡无关。因此，赋予多发性骨髓瘤细胞中低 CD38 表达选择压力的治疗策略可能具有临床益处。意义：这些结果突出了 miR-26a 通过靶向 CD38 发挥肿瘤抑制功能，并提示 miR-26a 在多发性骨髓瘤患者中的治疗潜力。
