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Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells

Oncogene volume 29, pages 1941–1951 (2010)Cite this article

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Abstract

Malignant pleural mesothelioma (MPM) is resistant to chemotherapy and thus shows a dismal prognosis. Osteopontin (OPN), a secreted noncollagenous and phosphoprotein, is suggested to be involved in the pathogenesis of MPM. However, the precise role of OPN, especially in the multidrug resistance of MPM, remains to be elucidated. We therefore established stable transfectants (ACC-MESO-1/OPN), which constitutively express OPN, to determine its role in the chemoresistance observed in MPM. The introduction of the OPN gene provides MPM cells with upregulated multidrug resistance through the mechanism of enhanced hyaluronate (HA) binding. The expression of CD44 variant isoforms, which inhibit HA binding, significantly decreased in ACC–MESO–1/OPN cells in comparison to control transfectants. Interestingly, the inhibition of the HA-CD44 interaction abrogated multidrug resistance in the ACC–MESO–1/OPN, thus suggesting the involvement of the surviving signal emanating from the HA-CD44 interaction. An enhanced level of the p-Akt in ACC–MESO–1/OPN cells was observed, and was diminished by CD44 siRNA. Inhibition of the Akt phosphorylation increased in number of the cells underwent apoptosis induced by NVB, VP-16 and GEM. Collectively, these results indicate that OPN is strongly involved in multidrug resistance by enhancing the CD44 binding to HA.

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Acknowledgements

This work was supported in part by a Grants-in-Aid for Cancer Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (K.T. No 19590914).

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Authors and Affiliations

  1. Department of Respiratory Medicine, Juntendo University, School of Medicine, Bunkyo-Ku, Tokyo, Japan

    K Tajima, R Ohashi, K Minakata, T Yae, F Takahashi & K Takahashi

  2. Research Institute for Diseases of Old Ages, Juntendo University, School of Medicine, Bunkyo-Ku, Tokyo, Japan

    K Tajima, R Ohashi, K Minakata, F Takahashi & K Takahashi

  3. Division of Molecular Oncology, Aichi Cancer Center Research Institute, Chikusa-ku, Nagoya, Japan

    Y Sekido & T Hida

  4. Department of Molecular and Cellular Parasitology, Juntendo University, School of Medicine, Bunkyo-Ku, Tokyo, Japan

    T Nara & M Hashimoto

  5. Department of Respiratory Medicine, Juntendo University Shizuoka Hospital, Shizuoka, Japan

    S Iwakami

  6. Division of Gene Regulation Institute for Advanced Medical Research School of Medicine, Keio University, Shinjuku-Ku, Tokyo, Japan

    T Yae & H Saya

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Correspondence to K Tajima.

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Tajima, K., Ohashi, R., Sekido, Y. et al. Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells. Oncogene 29, 1941–1951 (2010). https://doi.org/10.1038/onc.2009.478

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  • DOI: https://doi.org/10.1038/onc.2009.478

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