Ferroportin downregulation promotes cell proliferation by modulating the Nrf2-miR-17-5p axis in multiple myeloma
Ferroportin downregulation promotes cell proliferation by modulating the Nrf2-miR-17-5p axis in multiple myeloma
复制标题
铁转运蛋白下调通过调节多发性骨髓瘤中的 Nrf2-miR-17-5p 轴促进细胞增殖
DOI：
10.1038/s41419-019-1854-0
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发表时间：
2019-08-19
影响因子：
9
通讯作者：
Shi, Jumei
中科院分区：
文献类型：
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作者：
Kong, Yuanyuan;Hu, Liangning;Shi, Jumei
最近的研究结果表明，铁输出蛋白铁转运蛋白 (FPN1) 的异常下调与多发性骨髓瘤 (MM) 的不良预后和破骨细胞分化有关。在这里，我们发现 FPN1 在 MM 中下调，并且簇状规则间隔短回文重复 (CRISPR) 介导的 FPN1 敲除促进了 MM 细胞的生长和存活。使用 microRNA 靶扫描算法，我们将 miR-17-5p 确定为 FPN1 调节因子，可促进细胞增殖和细胞周期进展，并在体外和体内抑制细胞凋亡。 miR-17-5p 抑制 MM 异种移植模型中肿瘤生长的延迟。此外，恢复 FPN1 表达至少部分消除了 MM 细胞中 miR-17-5p 的生物学效应。细胞铁浓度通过 IRP 信使 RNA 的 5'-非翻译区调节铁调节蛋白 (IRP) 的表达，并调节 FPN1 的转录后稳定性。随后的染色质免疫沉淀-聚合酶链式反应和荧光素酶活性实验的生物信息学分析表明，转录因子 Nrf2 通过启动子结合驱动 FPN1 转录并抑制 miR-17-5p（这也增加了 FPN1 的表达）。 Nrf2 介导的 FPN1 下调促进细胞内铁积累和活性氧。我们的研究将 FPN1 转录和转录后调节与 MM 细胞生长和存活联系起来，并验证了 FPN1 的预后价值及其作为 MM 新型治疗靶点的实用性。
Recent findings demonstrate that aberrant downregulation of the iron-exporter protein, ferroportin (FPN1), is associated with poor prognosis and osteoclast differentiation in multiple myeloma (MM). Here, we show that FPN1 was downregulated in MM and that clustered regularly interspaced short palindromic repeat (CRISPR)-mediated FPN1 knockout promoted MM cell growth and survival. Using a microRNA target-scan algorithm, we identified miR-17-5p as an FPN1 regulator that promoted cell proliferation and cell cycle progression, and inhibited apoptosis both in vitro and in vivo. miR-17-5p inhibited retarded tumor growth in a MM xenograft model. Moreover, restoring FPN1 expression at least partially abrogated the biological effects of miR-17-5p in MM cells. The cellular iron concentration regulated the expression of the iron-regulatory protein (IRP) via the 5'-untranslated region of IRP messenger RNA and modulated the post-transcriptional stability of FPN1. Bioinformatics analysis with subsequent chromatin immunoprecipitation-polymerase chain reaction and luciferase activity experiments revealed that the transcription factor Nrf2 drove FPN1 transcription through promoter binding and suppressed miR-17-5p (which also increased FPN1 expression). Nrf2-mediated FPN1 downregulation promoted intracellular iron accumulation and reactive oxygen species. Our study links FPN1 transcriptional and post-transcriptional regulation with MM cell growth and survival, and validates the prognostic value of FPN1 and its utility as a novel therapeutic target in MM.