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MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene

Oncogene volume 32, pages 3019–3027 (2013)Cite this article

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Abstract

The purpose of this study was to define the roles of miR-181a in determining sensitivity of cervical cancer to radiation therapy, to explore the underlying mechanism and to evaluate the potential of miR-181a as a biomarker for predicting radio-sensitivity. Tumor specimens from 18 patients with a histological diagnosis of squamous cervical carcinoma (stage IIIB) were used in the micro-RNA profiling and comparison. These patients never received any chemotherapy before radiation therapy. Human cervical cancer cell lines, SiHa and Me180, were used in vitro (cell culture) and in vivo (animal) studies. Transfection of tumor cells with the mimic or inhibitor of miR-181a, and reporter gene assay, were performed to investigate the role of miR-181a in determining radio-sensitivity and the target gene. Higher expression of miR-181a was observed in human cervical cancer specimens and cell lines that were insensitive to radiation therapy, as compared with sensitive cancer specimens and the cell lines. We also found that miR-181a negatively regulated the expression of PRKCD, a pro-apoptotic protein kinase, via targeting its 3′-untranslated region (UTR), thereby inhibiting irradiation-induced apoptosis and decreasing G2/M block. The role of miR-181a in conferring cellular resistance to radiation treatment was validated both in cell culture models and in mouse tumor xenograft models. The effect of miR-181a on radio-resistance was mediated through targeting the 3′-UTR of PRKCD gene. Thus, the expression level of miR-181a in cervical cancer may serve as a biomarker for sensitivity to radiation therapy, and targeting miR-181a may represent a new approach to sensitizing cervical cancer to radiation treatment.

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Acknowledgements

We are most grateful for the pWPXL, psPAX2 and pMD2.Glentivirus plasmids that were provided by Professor Didier Trono from the School of Life Sciences, EcolePoly technique Fédérale de Lausanne, 1015 Lausanne, Switzerland. This work was supported by National Natural Science Foundation of China (No. 81072128), and Science and Technology Commission of Shanghai Municipality (Academic leader foundation of Shanghai, 09XD1401100).

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Authors and Affiliations

  1. Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, PR China

    G Ke, X Huang, D Han & X Wu

  2. Department of Oncology, Shanghai Medical College, Shanghai, PR China

    G Ke, X Huang, D Han & X Wu

  3. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China

    L Liang, S Huang, Y Zhao, R Zha & X He

  4. Department of Pharmacology and The Penn State Hershey Cancer Institute, The Pennsylvania State University College of Medicine and Milton S Hershey Medical Center, Hershey, PA, USA

    J M Yang

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  1. G Ke
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Correspondence to X He or X Wu.

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Ke, G., Liang, L., Yang, J. et al. MiR-181a confers resistance of cervical cancer to radiation therapy through targeting the pro-apoptotic PRKCD gene. Oncogene 32, 3019–3027 (2013). https://doi.org/10.1038/onc.2012.323

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