Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors. / Ostenfeld, Marie Stampe; Bramsen, J B; Lamy, P et al.
In: Oncogene, 2009.Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
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TY - JOUR
T1 - miR-145 induces caspase-dependent and -independent cell death in urothelial cancer cell lines with targeting of an expression signature present in Ta bladder tumors
AU - Ostenfeld, Marie Stampe
AU - Bramsen, J B
AU - Lamy, P
AU - Villadsen, Sune Bejerholm
AU - Fristrup, N
AU - Ulhøi, Benedicte Parm
AU - Borre, M
AU - Kjems, J
AU - Dyrskjøt, L
AU - Ørntoft, Torben Falck
PY - 2009
Y1 - 2009
N2 - Downregulation of miR-145 in a variety of cancers suggests a possible tumor suppressor function for this microRNA. Here, we show that miR-145 expression is reduced in bladder cancer and urothelial carcinoma in situ, compared with normal urothelium, using transcription profiling and in situ hybridization. Ectopic expression of miR-145 induced extensive apoptosis in urothelial carcinoma cell lines (T24 and SW780) as characterized by caspase activation, nuclear condensation and fragmentation, cellular shrinkage, and detachment. However, cell death also proceeded upon caspase inhibition by the pharmacological inhibitor zVAD-fmk and ectopic expression of anti-apoptotic Bcl-2, indicating the activation of an alternative caspase-independent death pathway. Microarray analysis of transcript levels in T24 cells, before the onset of cell death, showed destabilization of mRNAs enriched for miR-145 7mer target sites. Among these, direct targeting of CBFB, PPP3CA, and CLINT1 was confirmed by a luciferase reporter assay. Notably, a 22-gene signature targeted on enforced miR-145 expression in T24 cells was significantly (P<0.00003) upregulated in 55 Ta bladder tumors with concomitant reduction of miR-145. Our data indicate that reduction in miR-145 expression may provide bladder cancer cells with a selective advantage by inhibition of cell death otherwise triggered in malignant cells.Oncogene advance online publication, 16 November 2009; doi:10.1038/onc.2009.395.
AB - Downregulation of miR-145 in a variety of cancers suggests a possible tumor suppressor function for this microRNA. Here, we show that miR-145 expression is reduced in bladder cancer and urothelial carcinoma in situ, compared with normal urothelium, using transcription profiling and in situ hybridization. Ectopic expression of miR-145 induced extensive apoptosis in urothelial carcinoma cell lines (T24 and SW780) as characterized by caspase activation, nuclear condensation and fragmentation, cellular shrinkage, and detachment. However, cell death also proceeded upon caspase inhibition by the pharmacological inhibitor zVAD-fmk and ectopic expression of anti-apoptotic Bcl-2, indicating the activation of an alternative caspase-independent death pathway. Microarray analysis of transcript levels in T24 cells, before the onset of cell death, showed destabilization of mRNAs enriched for miR-145 7mer target sites. Among these, direct targeting of CBFB, PPP3CA, and CLINT1 was confirmed by a luciferase reporter assay. Notably, a 22-gene signature targeted on enforced miR-145 expression in T24 cells was significantly (P<0.00003) upregulated in 55 Ta bladder tumors with concomitant reduction of miR-145. Our data indicate that reduction in miR-145 expression may provide bladder cancer cells with a selective advantage by inhibition of cell death otherwise triggered in malignant cells.Oncogene advance online publication, 16 November 2009; doi:10.1038/onc.2009.395.
U2 - 10.1038/onc.2009.395
DO - 10.1038/onc.2009.395
M3 - Journal article
C2 - 19915607
JO - Oncogene
JF - Oncogene
SN - 0950-9232
ER -