miRNA-130a Targets ATG2B and DICER1 to Inhibit Autophagy and Trigger Killing of Chronic Lymphocytic Leukemia Cells
miRNA-130a Targets ATG2B and DICER1 to Inhibit Autophagy and Trigger Killing of Chronic Lymphocytic Leukemia Cells
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DOI：
10.1158/0008-5472.can-11-3671
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发表时间：
2012-04-01
期刊：
影响因子：
11.2
通讯作者：
Seiffert, Martina
中科院分区：
文献类型：
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作者：
Kovaleva, Valentina;Mora, Rodrigo;Seiffert, Martina
用于治疗慢性淋巴细胞白血病（CLL）的免疫化疗的毒性和复发促使人们对主要患有这种疾病的老年人群的温和但有效的靶向治疗选择持续感兴趣。在这里，我们报告的定义关键CLL细胞的生存途径，可以通过异位再表达的miRNA基因miR-130 a和miR-143，这是广泛下调CLL的目标。值得注意的是，miR-130 a通过减少自噬体形成来抑制自噬，这是由基因ATG 2B和DICER 1的下调介导的作用，后者是miRNA沉默机制的主要组分。为了支持这种癌症中miRNA失调和自噬通量改变之间存在根本联系的概念，我们表明RNA干扰介导的DICER 1表达敲低足以减少CLL细胞原代或已建立培养物中的自噬。总之，我们的研究结果表明，miR-130 a通过调节自噬通量来调节细胞存活程序，并且它们定义了miR-130 a和Dicer 1在介导CLL细胞存活的调节反馈回路中的作用。Cancer Res; 72（7）; 1763-72.（C）2012年AACR。
Toxicity and relapses from the immunochemotherapy used to treat chronic lymphocytic leukemia (CLL) prompt continued interest in gentle but effective targeted treatment options for the mainly elderly population suffering from this disease. Here, we report the definition of critical CLL cell survival pathways that can be targeted by ectopic reexpression of the miRNA genes miR-130a and miR-143 which are widely downregulated in CLL. Notably, miR-130a inhibited autophagy by reducing autophagosome formation, an effect mediated by downregulation of the genes ATG2B and DICER1, the latter of which is a major component of the miRNA silencing machinery. In support of the concept of a fundamental connection between miRNA disregulation and altered autophagic flux in this cancer, we showed that RNA interference-mediated knockdown of DICER1 expression was sufficient to reduce autophagy in primary or established cultures of CLL cells. Together, our findings show that miR-130a modulates cell survival programs by regulating autophagic flux, and they define roles for miR-130a and Dicer1 in a regulatory feedback loop that mediates CLL cell survival. Cancer Res; 72(7); 1763-72. (C)2012 AACR.