MicroRNA-142-3p inhibits cell proliferation in human acute lymphoblastic leukemia by targeting the MLL-AF4 oncogene
MicroRNA-142-3p inhibits cell proliferation in human acute lymphoblastic leukemia by targeting the MLL-AF4 oncogene
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DOI：
10.1007/s11033-013-2798-6
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发表时间：
2013-12-01
影响因子：
2.8
通讯作者：
Yu, Li
中科院分区：
文献类型：
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作者：
Dou, Liping;Li, Jingxin;Yu, Li
由染色体易位 t(4;11) 编码的混合谱系白血病 (MLL)-AF4 融合蛋白预测急性淋巴细胞白血病 (ALL) 的预后比其他 MLL 相关白血病的预后较差。然而，MLL-AF4 表达调节的详细机制仍然很大程度上未知。在这项研究中，我们发现表达 MLL-AF4 的 ALL 患者中 microRNA (miR)-142-3p 显着下调。 miR-142-3p 的上调降低了 RS4;11 白血病细胞系中 MLL-AF4 的表达，这表明 MLL-AF4 是 miR-142-3p 的直接靶标。 miR-142-3p 的异位表达显着抑制表达 MLL-AF4 融合蛋白的 RS4;11 细胞的细胞增殖并诱导细胞凋亡。我们还发现，外源表达 miR-142-3p 会强烈降低 RS4;11 细胞中 MLL-AF4 靶基因的表达，例如同源框 A (HOXA)9、HOXA7 和 HOXA10。综上所述，我们的结果表明 miR-142-3p 在 MLL-AF4(+) ALL 中充当生长抑制剂，其抑制作用主要通过抑制 MLL-AF4 表达来介导。
The mixed-lineage leukemia (MLL)-AF4 fusion protein encoded by the chromosomal translocation t(4;11) predicts a poorer prognosis in acute lymphoblastic leukemia (ALL) than in other MLL-associated leukemias. However, the detailed mechanism underlying regulation of MLL-AF4 expression remains largely unknown. In this study, we showed that microRNA (miR)-142-3p was significantly downregulated in ALL patients expressing MLL-AF4. Upregulation of miR-142-3p decreased MLL-AF4 expression in the RS4;11 leukemic cell line, which suggests that MLL-AF4 is a direct target of miR-142-3p. Ectopic expression of miR-142-3p remarkably suppressed cell proliferation and induced apoptosis in RS4;11 cells expressing the MLL-AF4 fusion protein. We also found that exogenous expression of miR-142-3p strongly reduced the expression of MLL-AF4 target genes such as homeobox A (HOXA)9, HOXA7, and HOXA10 in RS4;11 cells. Taken together, our results indicate that miR-142-3p functions as a growth suppressor in MLL-AF4(+) ALL, and its suppressive effects are mediated primarily through repression of MLL-AF4 expression.