Runx2 Suppression by miR-342 and miR-363 Inhibits Multiple Myeloma Progression.
Runx2 Suppression by miR-342 and miR-363 Inhibits Multiple Myeloma Progression.
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DOI：
10.1158/1541-7786.mcr-17-0606
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发表时间：
2018-07
期刊：
影响因子：
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通讯作者：
Yang Y
中科院分区：
文献类型：
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作者：
Gowda PS;Wildman BJ;Trotter TN;Xu X;Hao X;Hassan MQ;Yang Y
在多发性骨髓瘤（MM）中，异常浆细胞在骨髓中积聚和增殖。最近，我们观察到Runx 2是一种骨特异性转录因子，在MM细胞中高度表达，是MM在骨中进展的主要驱动因素。本研究的主要目标是鉴定可以减少肿瘤生长的Runx 2靶向miRNA。与健康对照标本相比，MM患者标本中一组miRNA的表达分析显示，转移性MM细胞表达低水平的miR-342和miR-363，但高水平的Runx 2。用miR-342和miR-363重建MM细胞（CAG）降低了Runx 2的丰度和促进转移的Runx 2靶基因RANKL和DKK 1的表达，并抑制了Runx 2下游信号通路Akt/β-catenin/survivin，这是MM肿瘤进展所必需的。将单独或一起稳定过表达miR-342和miR-363的MM细胞（5 TGM 1）静脉注射到同基因C57 Bl/KaLwRij小鼠中，与注射表达miR-Scramble对照的5 TGM 1细胞的小鼠相比，骨髓中5 TGM 1细胞生长受到显著抑制，破骨细胞减少，成骨细胞增加，抗肿瘤免疫力增加。总之，这些结果表明，MM细胞中miR-342和miR-363的表达增强抑制Runx 2表达和MM生长，减少骨质溶解，并增强抗肿瘤免疫力。因此，在MM细胞中恢复miR-342和miR-363的Runx 2靶向功能可以通过预防MM进展提供治疗益处。miR-342和miR-363介导的MM细胞中Runx 2表达下调可预防MM进展。
In multiple myeloma (MM), abnormal plasma cells accumulate and proliferate in the bone marrow. Recently, we observed that Runx2, a bone-specific transcription factor, is highly expressed in MM cells and is a major driver of MM progression in bone. The primary goal of the present study was to identify Runx2-targeting miRNAs that can reduce tumor growth. Expression analysis of a panel of miRNAs in MM patient specimens, compared with healthy control specimens, revealed that metastatic MM cells express low levels of miR-342 and miR-363 but high levels of Runx2. Reconstituting MM cells (CAG) with miR-342 and miR-363 reduced the abundance of Runx2 and the expression of metastasis-promoting Runx2 target genes RANKL and DKK1, and suppressed Runx2-downstream signaling pathways Akt/β-catenin/survivin, which are required for MM tumor progression. Intravenous injection of MM cells (5TGM1), stably overexpressing miR-342 and miR-363 alone or together, into syngenic C57Bl/KaLwRij mice resulted in a significant suppression of 5TGM1 cell growth, decreased osteoclasts and increased osteoblasts, and increased anti-tumor immunity in the bone marrow, compared to mice injected with 5TGM1 cells expressing a miR-Scramble control. In summary, these results demonstrate that enhanced expression of miR-342 and miR-363 in MM cells inhibits Runx2 expression and MM growth, decreases osteolysis, and enhances anti-tumor immunity. Thus, restoring the function of Runx2-targeting by miR-342 and miR-363 in MM cells may afford a therapeutic benefit by preventing MM progression. miR-342 and miR-363-mediated downregulation of Runx2 expression in MM cells prevents MM progression.