MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R
MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R
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DOI：
10.1038/onc.2012.318
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发表时间：
2013-06-20
期刊：
影响因子：
8
通讯作者：
Zhuang, S-M
中科院分区：
文献类型：
--
作者：
Gong, J.;Zhang, J-P;Zhuang, S-M
microRNA miR-125 b是多方面的，具有作为肿瘤抑制因子或癌基因发挥作用的能力，这取决于细胞环境。迄今为止，miR-125 b的促凋亡作用及其潜在机制尚未探索。在这项研究中，功能获得和功能丧失实验都表明，miR-125 b表达不仅诱导了来自肝癌、肺癌和结直肠癌的各种细胞系的自发凋亡，而且还使癌细胞对各种凋亡刺激物敏感，包括营养饥饿和化疗治疗。此外，miR-125 b的下调是肝细胞癌（HCC）组织中常见的事件，并且miR-125 b水平与HCC组织中的凋亡率呈正相关。随后的研究将Mcl-1、Bcl-w和白细胞介素（IL）-6R确定为miR-125 b的直接靶点。miR-125 b表达的恢复不仅直接降低了Mcl-1和Bcl-w的表达，而且通过减弱IL-6/信号转导子和转录激活子3信号转导而间接降低了Mcl-1和Bcl-xL的水平。与这些发现一致，miR-125 b的引入降低了线粒体膜电位并促进了caspase-3原的切割。这些数据表明，miR-125 b可以通过抑制Bcl-2家族的抗凋亡分子来促进凋亡，并且miR-125 b下调可以通过赋予细胞在营养剥夺和化疗治疗的条件下存活的能力来促进肿瘤发展。我们的研究结果强调了miR-125 b在细胞凋亡调控中的重要性，并表明miR-125 b是一个有吸引力的抗癌治疗靶点。
The microRNA miR-125b is multi-faceted, with the ability to function as a tumor suppressor or an oncogene, depending on the cellular context. To date, the pro-apoptotic role of miR-125b and its underlying mechanisms are unexplored. In this study, both gain-and loss-of-function experiments revealed that miR-125b expression not only induced spontaneous apoptosis in various cell lines derived from the liver, lung and colorectal cancers, but also sensitized cancer cells to diverse apoptotic stimuli, including nutrient starvation and chemotherapeutic treatment. Furthermore, downregulation of miR-125b was a frequent event in hepatocellular carcinoma (HCC) tissues, and the miR-125b level was positively associated with the rate of apoptosis in HCC tissues. Subsequent investigations identified Mcl-1, Bcl-w and interleukin (IL)-6R as direct targets of miR-125b. Restoration of miR-125b expression not only diminished the expression of Mcl-1 and Bcl-w directly but also indirectly reduced the Mcl-1 and Bcl-xL levels by attenuating IL-6/signal transducer and activator of transcription 3 signaling. Consistent with these findings, introduction of miR-125b reduced the mitochondrial membrane potential and promoted the cleavage of pro-caspase-3. These data indicate that miR-125b may promote apoptosis by suppressing the anti-apoptotic molecules of the Bcl-2 family and miR-125b downregulation may facilitate tumor development by conferring upon cells the capability to survive under conditions of nutrient deprivation and chemotherapeutic treatment. Our findings highlight the importance of miR-125b in the regulation of apoptosis and suggest miR-125b as an attractive target for anti-cancer therapy.