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

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, Jesper Bertram

AU - Lamy, Philippe

AU - Villadsen, Sune Bejerholm

AU - Fristrup, Niels

AU - Dalsgaard Sørensen, Karina

AU - Ulhøi, Benedicte Parm

AU - Borre, Michael

AU - Kjems, Jørgen

AU - Andersen, Lars Dyrskjøt

AU - Ørntoft, Torben Falck

PY - 2010/2/18

Y1 - 2010/2/18

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.

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.

U2 - 10.1038/onc.2009.395

DO - 10.1038/onc.2009.395

M3 - Journal article

C2 - 19915607

SN - 0950-9232

VL - 29

SP - 1073

JO - Oncogene

JF - Oncogene

IS - 7

ER -