Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Differ. 2013 Mar;20(3):408-18. doi: 10.1038/cdd.2012.130. Epub 2012 Oct 12.
Hypoxia-inducible factor 1 (HIF-1) is a crucial transcription factor for the cellular adaptive response to hypoxia, which contributes to multiple events in cancer biology. MicroRNAs (miRNAs) are involved in almost all cellular activities such as differentiation, proliferation, and apoptosis. In this work, we use miRNA microarrays to profile miRNA expression in acute myeloid leukemia (AML) cells with inducible HIF-1α expression, and identify 19 differentially expressed miRNAs. Our study shows that HIF-1α represses the expression of miR-17 and miR-20a by downregulating c-Myc expression. These two miRNAs alleviate hypoxia and HIF-1α-induced differentiation of AML cells. More intriguingly, miR-17 and miR-20a directly inhibit the p21 and STAT3 (signal transducer and activator of transcription 3) expression, both of which can reverse miR-17/miR-20a-mediated abrogation of HIF-1α-induced differentiation. Moreover, we show in vivo that miR-20a contributes to HIF-1α-induced differentiation of leukemic cells. Taken together, our results suggest that HIF-1α regulates the miRNA network to interfere with AML cell differentiation, representing a novel molecular mechanism for HIF-1-mediated anti-leukemic action.
缺氧诱导因子 1（HIF-1）是细胞对缺氧适应性反应的关键转录因子，有助于癌症生物学中的多种事件。微小 RNA（miRNA）参与几乎所有的细胞活动，如分化、增殖和凋亡。在这项工作中，我们使用 miRNA 微阵列来描绘具有诱导性 HIF-1α表达的急性髓系白血病（AML）细胞中的 miRNA 表达谱，并鉴定出 19 个差异表达的 miRNA。我们的研究表明，HIF-1α 通过下调 c-Myc 表达来抑制 miR-17 和 miR-20a 的表达。这两个 miRNA 缓解了缺氧和 HIF-1α诱导的 AML 细胞分化。更有趣的是，miR-17 和 miR-20a 直接抑制 p21 和 STAT3（信号转导和转录激活因子 3）的表达，这两者都可以逆转 miR-17/miR-20a 介导的 HIF-1α诱导分化的阻断。此外，我们在体内证明 miR-20a 有助于 HIF-1α 诱导的白血病细胞分化。总之，我们的结果表明，HIF-1α 调节 miRNA 网络来干扰 AML 细胞分化，代表了 HIF-1 介导的抗白血病作用的新分子机制。
