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

H. Ebi, T. Sato, N. Sugito, Y. Hosono, Y. Yatabe, Y. Matsuyama, T. Yamaguchi, H. Osada, M. Suzuki, T. Takahashi

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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.

Original languageEnglish
Pages (from-to)3371-3379
Number of pages9
JournalOncogene
Volume28
Issue number38
DOIs
Publication statusPublished - 24-09-2009

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Ebi, H., Sato, T., Sugito, N., Hosono, Y., Yatabe, Y., Matsuyama, Y., Yamaguchi, T., Osada, H., Suzuki, M., & Takahashi, T. (2009). Counterbalance between RB inactivation and miR-17-92 overexpression in reactive oxygen species and DNA damage induction in lung cancers. Oncogene, 28(38), 3371-3379. https://doi.org/10.1038/onc.2009.201