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MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R

Oncogene volume 32, pages 3071–3079 (2013)Cite this article

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Abstract

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.

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Acknowledgements

This study was supported by grants from the Ministry of Science and Technology of China (2010CB912803 and 2011CB811305), the Ministry of Health of China (2012ZX10002-011) and the National Natural Science Foundation of China (30925036).

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  1. J Gong and J-P Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory of Biocontrol, School of Life Sciences, Guangzhou, PR China

    J Gong, J-P Zhang, C Zeng, K You & S-M Zhuang

  2. Department of Hepatobiliary Oncology, State Key Laboratory of Oncology in Southern China, Cancer Center, Sun Yat-sen University, Guangzhou, PR China

    B Li, M-X Chen & Y Yuan

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  1. J Gong
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Correspondence to Y Yuan or S-M Zhuang.

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Gong, J., Zhang, JP., Li, B. et al. MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R. Oncogene 32, 3071–3079 (2013). https://doi.org/10.1038/onc.2012.318

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