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Counterbalance between RB inactivation and miR-17–92 overexpression in reactive oxygen species and DNA damage induction in lung cancers

Oncogene volume 28, pages 3371–3379 (2009)Cite this article

Abstract

Small-cell lung cancer (SCLC) is a highly aggressive disease that exhibits rapid growth and genetic instability. We found earlier frequent overexpression of the miR-17–92 microRNA cluster, and showed that SCLC cells were addicted to continued expressions of miR-17–5p and miR-20a, major components of this microRNA cluster. In this study, we identified the frequent presence of constitutively phosphorylated H2AX (γ-H2AX), which reflects continuing DNA damage, preferentially in SCLC. Knockdown of RB induced γ-H2AX foci formation in non-small cell lung cancer (NSCLC) cells with wild-type RB, in association with growth inhibition and reactive oxygen species (ROS) generation, which was canceled by overexpression of miR-17–92. Conversely, induction of γ-H2AX was observed in a miR-17–92-overexpressing SCLC cell line with miR-20a antisense oligonucleotides. These findings suggest that miR-17–92 overexpression may serve as a fine-tuning influence to counterbalance the generation of DNA damage in RB-inactivated SCLC cells, thus reducing excessive DNA damage to a tolerable level and consequently leading to genetic instability. Therefore, miR-17–92 may be an excellent therapeutic target candidate to elicit excessive DNA damage in combination with DNA-damaging chemotherapeutics.

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Acknowledgements

This work was financially supported in part by a Grant-in-Aid for Scientific Research on priority areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan, a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, and a Grant (07–23903) from the Princess Takamatsu Cancer Research Fund. HE was supported by the IASLC fellowship of the International Association for the Study of Lung Cancer (IASLC) during this study.

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  1. H Ebi and T Sato: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan

    H Ebi, T Sato, N Sugito, Y Hosono, Y Matsuyama, T Yamaguchi, M Suzuki & T Takahashi

  2. Department of Pathology and Molecular Diagnosis, Aichi Cancer Center Hospital, Showa-ku, Nagoya, Japan

    Y Yatabe

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

    H Osada

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Correspondence to T Takahashi.

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Supplementary information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Ebi, H., Sato, T., Sugito, N. et al. Counterbalance between RB inactivation and miR-17–92 overexpression in reactive oxygen species and DNA damage induction in lung cancers. Oncogene 28, 3371–3379 (2009). https://doi.org/10.1038/onc.2009.201

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