Prognostic significance of Dicer expression in ovarian cancer-link to global microRNA changes and oestrogen receptor expression.
MicroRNA (miRNA) deregulation is a hallmark of human cancer. However, the mechanisms underlying miRNA alteration and the specific role of proteins involved in miRNA processing remains to be elucidated. Dicer is a key enzyme in the miRNA processing pathway that is essential for the production of mature miRNAs from their precursors. We tested the hypothesis that Dicer has biological and clinical relevance in ovarian cancer, using a range of methods including in vitro manipulation of Dicer expression. We observed down-regulation of Dicer in a subgroup of ovarian carcinomas, and found that decreased Dicer expression correlates significantly with reduced patient survival in serous cancers and advanced disease stages. Moreover, microarray and functional analysis suggest that reduced Dicer expression is connected with a global down-regulation of the microRNAome and with gene expression changes, particularly reduced expression of oestrogen receptor (ER) mRNA and protein in tumour tissue and in cell culture. Our data suggest a common mechanism for miRNAs changes by alterations in the basic machinery controlling miRNA biogenesis, of which Dicer is a central enzyme. These alterations of miRNA processing are of prognostic value and may play a role in the molecular pathogenesis of ovarian carcinoma and, possibly, other tumours. Knowledge of these molecular pathways may help toward new targeted therapeutic approaches for ovarian cancer.
Faggad
Areeg
A
Institute of Pathology, Charité University Hospital, 10117 Berlin, Germany.
Budczies
Jan
J
Tchernitsa
Oleg
O
Darb-Esfahani
Silvia
S
Sehouli
Jalid
J
Müller
Berit M
BM
Wirtz
Ralph
R
Chekerov
Radoslav
R
Weichert
Wilko
W
Sinn
Bruno
B
Mucha
Christin
C
Elwali
Nasr E
NE
Schäfer
Reinhold
R
Dietel
Manfred
M
Denkert
Carsten
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D055785:Gene Knockdown Techniques; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D012334:RNA, Neoplasm / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism*; D043244:Ribonuclease III / Q000378:metabolism*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D043244:Ribonuclease III