miR-96 acts as a tumor suppressor via targeting the BCR-ABL1 oncogene in chronic myeloid leukemia blastic transformation
miR-96 acts as a tumor suppressor via targeting the BCR-ABL1 oncogene in chronic myeloid leukemia blastic transformation
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miR-96 通过靶向慢性粒细胞白血病母细胞转化中的 BCR-ABL1 癌基因发挥肿瘤抑制因子的作用。
DOI：
10.1016/j.biopha.2019.109413
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发表时间：
2019-11-01
影响因子：
7.5
通讯作者：
Chen, Chunyan
中科院分区：
文献类型：
--
作者：
Huang, Tao;Fu, Yue;Chen, Chunyan
MicroRNA介导的转录后调控是基因表达的重要表观遗传调控机制，其失调参与多种恶性肿瘤的发生和进展，包括慢性粒细胞白血病（CML）。 BCR-ABL1融合基因不仅是CML的起始因素，也是急变转化的重要驱动因素。以伊马替尼为代表的针对BCR-ABL1酪氨酸激酶活性的酪氨酸激酶抑制剂（TKI）是目前治疗CML的一线药物。但由于BCR-ABL1激酶结构域突变引起的原发耐药或继发耐药，TKIs并不能完全阻止CML的进展；因此，BCR-ABL1基因表达调控的研究具有重要意义。在本研究中，生物信息学分析和我们的结果表明，miR-96可以直接结合BCR-ABL1的3'UTR区域来调节融合蛋白的表达，从而调节其下游信号通路活性。我们还发现，在从慢性期（CML-CP）到急变期（CML-BC）的过程中，miR-96 下调。下调miR-96可促进CML-BC细胞增殖并参与细胞分化。此外，我们发现新型组蛋白脱乙酰酶药物西达本胺和DNA甲基转移酶抑制剂地西他滨可以恢复CML细胞中miR-96的低表达，并且CML细胞中miR-96的启动子区域存在两个异常高甲基化位点，表明其低表达可能至少部分受到表观遗传机制的调节。此外，miR-96的重新表达可以增加CML-BC细胞对伊马替尼的敏感性。因此，miR-96 作为肿瘤抑制因子发挥作用，并且这种 microRNA 的重新表达可能在 CML 急变转化中具有治疗益处。
MicroRNA-mediated posttranscriptional regulation is an important epigenetic regulatory mechanism of gene expression, and its dysregulation is involved in the development and progression of a variety of malignancies, including chronic myeloid leukemia (CML). The BCR-ABL1 fusion gene is not only the initiating factor of CML, but it is also an important driving factor for blastic transformation. Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 tyrosine kinase activity, represented by imatinib, are currently the first-line treatment for CML. However, due to primary resistance or secondary resistance caused by mutations in the BCR-ABL1 kinase domain, TKIs cannot completely prevent the progression of CML; thus, the study of BCR-ABL1 gene expression regulation is of great significance. In this study, bioinformatics analysis and our results showed that miR-96 could directly bind to the 3'UTR region of BCR-ABL1 to regulate fusion protein expression, thereby regulating its downstream signaling pathway activity. We also found that miR-96 was downregulated during the progression from the chronic phase (CML-CP) to the blast crisis (CML-BC). Downregulation of miR-96 could promote the proliferation and participate in the cell differentiation of CML-BC cells. Additionally, we found that the novel histone deacetylase drug chidamide and the DNA methyltransferase inhibitor decitabine could restore the low expression of miR-96 in CML cells, and there were two abnormal hypermethylated sites in the promoter region of miR-96 in CML, suggesting that its low expression might be at least partially regulated by epigenetic mechanisms. In addition, re-expression of miR-96 could increase the sensitivity of CML-BC cells to imatinib. Thus, miR-96 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in CML blastic transformation.