Counterbalance between RB inactivation and miR-17-92 overexpression in reactive oxygen species and DNA damage induction in lung cancers.
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 (gamma-H2AX), which reflects continuing DNA damage, preferentially in SCLC. Knockdown of RB induced gamma-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 gamma-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.
Ebi
H
H
Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Japan.
Sato
T
T
Sugito
N
N
Hosono
Y
Y
Yatabe
Y
Y
Matsuyama
Y
Y
Yamaguchi
T
T
Osada
H
H
Suzuki
M
M
Takahashi
T
T
D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000502:physiology; D004249:DNA Damage; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D035683:MicroRNAs / Q000502:physiology*; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000502:physiology*
D019927:Cyclin E; C468783:H2AX protein, human; D006657:Histones; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D017382:Reactive Oxygen Species; D016160:Retinoblastoma Protein; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2