Apoptosis induction by antisense oligonucleotides against miR-17-5p and miR-20a in lung cancers overexpressing miR-17-92.
Amplification and overexpression of the miR-17-92 microRNAs (miRNA) cluster at 13q31.3 has recently reported, with pointers to functional involvement in the development of B-cell lymphomas and lung cancers. In the present study, we show that inhibition of miR-17-5p and miR-20a with antisense oligonucleotides (ONs) can induce apoptosis selectively in lung cancer cells overexpressing miR-17-92, suggesting the possibility of 'OncomiR addiction' to expression of these miRNAs in a subset of lung cancers. In marked contrast, antisense ONs against miR-18a and miR-19a did not exhibit such inhibitory effects, whereas inhibition of miR-92-1 resulted in only modest reduction of cell growth, showing significant distinctions among miRNAs of the miR-17-92 cluster in terms of their roles in cancer cell growth. During the course of this study, we also found that enforced expression of a genomic region, termed C2, residing 3' to miR-17-92 in the intron 3 of C13orf25 led to marked growth inhibition in association with double stranded RNA-dependent protein kinase activation. Finally, this study also revealed that the vast majority of C13orf25 transcripts are detected as Drosha-processed cleavage products on Northern blot analysis and that a novel polyadenylation site is present 3' to the miR-17-92 cluster and 5' to the C2 region. Taken together, the present findings contribute towards better understanding of the oncogenic roles of miR-17-92, which might ultimately lead to the future translation into clinical applications.
Matsubara
H
H
Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.
Takeuchi
T
T
Nishikawa
E
E
Yanagisawa
K
K
Hayashita
Y
Y
Ebi
H
H
Yamada
H
H
Suzuki
M
M
Nagino
M
M
Nimura
Y
Y
Osada
H
H
Takahashi
T
T
D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002882:Chromosomes, Human, Pair 13; D006801:Humans; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016366:Open Reading Frames; D014158:Transcription, Genetic
D035683:MicroRNAs; D016376:Oligonucleotides, Antisense