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Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop

Oncogene volume 32, pages 61–69 (2013)Cite this article

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Abstract

Dysregulated microRNAs (miRNAs) have an important role in many malignant tumors. However, elucidating the roles of miRNAs in cancer biology, especially in epithelial cancers, remains an ongoing process. In this study, we show that both miR-143 and miR-145, which belong to the same miRNA cluster, can negatively modulate expression of their target gene, MDM2. The miR-143 and miR-145 is posttranscriptionally activated by upregulated p53, thereby generating a short miRNAs-MDM2-p53 feedback loop. Re-expression of these miRNAs suppresses cellular growth and triggers the apoptosis of epithelial cancer, in vitro and in vivo, by enhancing p53 activity via MDM2 turnover. Moreover, the miRNA-dependent MDM2 turnover contributes to the equilibrium of repeated p53 pulses in response to DNA damage stress. These findings suggest that MDM2 dysregulation caused by downregulation of miR-143 and miR-145 contributes to epithelial cancer development and has a key role in regulating cellular proliferation and apoptosis. Re-expression of miR-143 and miR-145 may be a reasonable strategy for treatment of epithelial cancers.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (Grant No. 30973343 and 81101515), Projects of the Shanghai Science and Technology Committee (Grant No. 08JC1414400, 11DZ2291800, 10DZ1951300 and 10XD1402500), the Shanghai Leading Academic Discipline Project (S30206), the Program of Shanghai Municipal Education Commission (12YZ052 and shjdy027) and National Basic Research Program of China (2010CB529204).

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Authors and Affiliations

  1. Department of Oral and Maxillofacial Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China

    J Zhang, Q Sun, Z Zhang, S Ge & W-T Chen

  2. Shanghai Key Laboratory of Stomatology, Shanghai, PR China

    J Zhang, Z Zhang, Z-G Han & W-T Chen

  3. Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, PR China

    Z-G Han

  4. These authors contributed equally to this work,

    J Zhang & Q Sun

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  1. J Zhang
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Correspondence to W-T Chen.

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Zhang, J., Sun, Q., Zhang, Z. et al. Loss of microRNA-143/145 disturbs cellular growth and apoptosis of human epithelial cancers by impairing the MDM2-p53 feedback loop. Oncogene 32, 61–69 (2013). https://doi.org/10.1038/onc.2012.28

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