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MiR-152 and miR-185 co-contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine

Oncogene volume 33, pages 378–386 (2014)Cite this article

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Abstract

Epithelial ovarian cancer (EOC) is a highly lethal gynaecological malignancy. Cisplatin is the basal chemotherapeutic agent used to treat EOC, but resistance to cisplatin leads to chemotherapy failure. MicroRNAs are a novel class of regulators that function by controlling gene expression at the post-transcriptional level. Several recent reports have identified some microRNAs that are related to chemotherapy sensitivity. In this study, we found two microRNAs miR-152 and miR-185 that were significantly downregulated in the cisplatin-resistant ovarian cell lines SKOV3/DDP and A2780/DDP, compared with their sensitive parent line SKOV3 and A2780, respectively. Subsequently, the roles of miR-152 and miR-185 were evaluated in vitro and in vivo. The overexpression of miR-152 or miR-185 increased cisplatin sensitivity of SKOV3/DDP and A2780/DDP cells by inhibiting proliferation and promoting apoptosis, then we further confirmed that these miRNAs functioned through suppressing DNA methyltransferase 1 (DNMT1) directly. Concordantly, CD-1/CD-1 nude mice that were injected intraperitoneally with SKOV3/DDP cells transfected with miR-152 mimics exhibited upregulated cisplatin sensitivity in vivo. Interestingly, we found that there were no significant changes in the expression of these two microRNAs after treatment with decitabine (DAC), a traditional epigenetic therapeutic agent, suggesting these miRNAs represented two new regulators independent of DAC. Finally, the survival assay in A549 and HepG2 cells revealed that the two microRNAs involved in cisplatin sensitivity were related to cell types. Our results indicated that miR-152 and miR-185 were involved in ovarian cancer cisplatin resistance in vitro and in vivo by targeting DNMT1 directly. These molecules may serve as potential epigenetic therapeutic targets in other cancers.

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Acknowledgements

This work was supported by the Natural Science Foundation of Heilongjiang Province for youth (QC2010002) and for outstanding youth (JC201110), the Natural Science Foundation of China (81101373/81270511/81001033), the Science Foundation of Health Department of Heilongjiang Province(2012-525) and the Science Foundation of the First Affiliated Hospital of Harbin Medical University (2009Y24).

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  1. Y Xiang, N Ma and D Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China

    Y Xiang, N Ma, D Wang, J Zhou, G Wu, R Zhao, H Huang, X Wang, Y Qiao, F Li, D Han, L Wang & X Gao

  2. Department of Laboratory Diagnosis, First Affiliated Hospital of Harbin Medical University, Harbin, China

    Y Zhang

  3. Department of Obstetrics and Gynecology, First Affiliated Hospital of Harbin Medical University, Harbin, China

    G Zhang

  4. Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, Harbin, China

    X Gao

  5. State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin, China

    X Gao

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Xiang, Y., Ma, N., Wang, D. et al. MiR-152 and miR-185 co-contribute to ovarian cancer cells cisplatin sensitivity by targeting DNMT1 directly: a novel epigenetic therapy independent of decitabine. Oncogene 33, 378–386 (2014). https://doi.org/10.1038/onc.2012.575

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