TY - JOUR
T1 - Counterbalance between RB inactivation and miR-17-92 overexpression in reactive oxygen species and DNA damage induction in lung cancers
AU - Ebi, H.
AU - Sato, T.
AU - Sugito, N.
AU - Hosono, Y.
AU - Yatabe, Y.
AU - Matsuyama, Y.
AU - Yamaguchi, T.
AU - Osada, H.
AU - Suzuki, M.
AU - Takahashi, T.
N1 - Funding Information:
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.
PY - 2009/9/24
Y1 - 2009/9/24
N2 - 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.
AB - 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.
KW - DNA damage response
KW - MiRNA
KW - RB
KW - Reactive oxygen species
KW - Small-cell lung cancer
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U2 - 10.1038/onc.2009.201
DO - 10.1038/onc.2009.201
M3 - Article
C2 - 19597473
AN - SCOPUS:70349464806
SN - 0950-9232
VL - 28
SP - 3371
EP - 3379
JO - Oncogene
JF - Oncogene
IS - 38
ER -
