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miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo

Oncogene volume 30, pages 4386–4398 (2011)Cite this article

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Abstract

Cancer cell resistance to paclitaxel continues to be a major clinical problem. In this study, we utilized microRNA (miRNA) arrays to screen for differentially expressed miRNAs in paclitaxel-resistant cell lines established in vitro. We observed concordant upregulation of miR-135a in paclitaxel-resistant cell lines representing three human malignancies. Subsequently, the role of miRNA-135a was evaluated in an in vivo model of paclitaxel resistance. In this model, mice were inoculated subcutaneously with a non-small cell lung carcinoma cell line and treated with paclitaxel for a prolonged period. In paclitaxel-resistant cell lines, established either in vitro or in vivo, blockage of miR-135a sensitized resistant cell lines to paclitaxel-induced cell death. We further demonstrated a correlation between paclitaxel response and miR-135a expression in paclitaxel-resistant subclones that were established in vivo. The paclitaxel-resistant phenotype of these subclones was maintained upon retransplantation in new mice, as shown by decreased tumor response upon paclitaxel treatment compared with controls. Upregulation of miR-135a was associated with reduced expression of the adenomatous polyposis coli gene (APC). APC knockdown increased paclitaxel resistance in parental cell lines. Our results indicate that paclitaxel resistance is associated with upregulation of miR-135a, both in vitro and in vivo, and is in part determined by miR-135a-mediated downregulation of APC.

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Acknowledgements

We sincerely thank Dr John Heymach of MD Anderson Cancer Institute, Houston, TX and Jeremy Force, Children's Hospital Boston, for kindly providing us with the A549TR cells. This work was supported in part by grant CA37393 from the National Institutes of Health (BRZ), Kendle (AH), KWF Cancer Foundation (AH), the Stichting Fonds Catherine van Tussenbroek (AH), and a US Department of Defense PCRP fellowship (IC).

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  1. A Holleman and I Chung: These authors contributed equally to this work.

Authors and Affiliations

  1. Vascular Biology Program, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA

    A Holleman, I Chung, R R Olsen, B Kwak & B R Zetter

  2. Department of Internal Medicine,

    A Holleman

  3. Meander Medical Center, Amersfoort, The Netherlands

    A Holleman

  4. Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan

    A Mizokami

  5. Medical Oncology Division, National Cancer Center Research Institute, Tokyo, Japan

    N Saijo

  6. Regional Cancer Program, Hôpital Régional de Sudbury Regional Hospital, Sudbury, Ontario, Canada

    A Parissenti

  7. Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, USA

    Z Duan

  8. Department of Medical Oncology,

    E E Voest

  9. Utrecht Medical Center, Utrecht, The Netherlands

    E E Voest

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Holleman, A., Chung, I., Olsen, R. et al. miR-135a contributes to paclitaxel resistance in tumor cells both in vitro and in vivo. Oncogene 30, 4386–4398 (2011). https://doi.org/10.1038/onc.2011.148

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