Prognostic significance of Dicer expression in ovarian cancer—link to global microRNA changes and oestrogen receptor expression

Abstract

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.

Clinicopathological and prognostic significance of the microRNA processing enzyme DICER1 mRNA expression in colorectal cancer patients

“…However, the protein expression was not informative for survival. Of note, our data showed that low expression levels of DICER1 mRNA in CRC tissues significantly correlate with poorer OS and DFS, thereby supporting the findings of Faggad et al (36). The expression level of DICER1 directly influences the biosynthesis of miRNA.…”

Geminin facilitates FoxO3 deacetylation to promote breast cancer cell metastasis

“…We report here that geminin promotes tumor invasion jci. (52,53). Indeed, Dicer levels were remarkably decreased in grade III as well as the invasive breast cancers, which inversely correlated with elevated geminin and/or HDAC3 levels.…”

Comprehensive evaluation of canonical versus Dicer-substrate siRNA in vitro and in vivo

“…Dicer has been shown to be regulated, both up and down, in various cancers (Merritt et al 2008(Merritt et al , 2010Catto et al 2009;Faggad et al 2010;Watashi et al 2010;Wu et al 2010), and reduced Dicer expression is associated with reduced survival in patients with ovarian cancer (Merritt et al 2008). Additionally, cellular stresses affect Dicer levels in vitro (Wiesen and Tomasi 2009), and, as expected, dsiRNAs are less effective in diseased tissue with down-regulated Dicer (Merritt et al 2008).…”