Dicer, Drosha, and Outcomes in Patients with Ovarian Cancer

By W. Merritt, Yvonne G Lin, Liz Y. Han, Aparna A. Kamat, W. Spannuth, R. Schmandt, D. Urbauer, Len A. Pennacchio, Jan-Fang Cheng, A. Nick and 12 more. New England Journal of Medicine, 2008

740 citations recorded by the source corpus.

Background We studied Dicer and Drosha, components of the RNA-interference machinery, in ovarian cancer. Methods We measured messenger RNA (mRNA) levels of Dicer and Drosha in specimens of invasive epithelial ovarian cancer from 111 patients, using a quantitative reverse-transcriptase–polymerase-chain-reaction assay, and compared the results with clinical outcomes. Validation was performed with the use of published microarray data from cohorts of patients with ovarian, breast, and lung cancer. Mutational analyses of genomic DNA from the Dicer and Drosha genes were performed in a subgroup of ovarian-cancer specimens. Dicer-dependent functional assays were performed by means of in vitro transfection with small interfering RNA (siRNA) and short hairpin RNA (shRNA). Results Levels of Dicer and Drosha mRNA correlated with the levels of expression of the corresponding protein and were decreased in 60% and 51% of ovarian-cancer specimens, respectively. Low Dicer expression was significantly associated with advanced tumor stage (P = 0.007), and low Drosha expression with suboptimal surgical cytoreduction (P = 0.02). Cancer specimens with both high Dicer expression and high Drosha expression were associated with increased median survival (>11 years, vs. 2.66 years for other subgroups; P<0.001). We found three independent predictors of reduced disease-specific survival in multivariate analyses: low Dicer expression (hazard ratio, 2.10; P = 0.02), high-grade histologic features (hazard ratio, 2.46; P = 0.03), and poor response to chemotherapy (hazard ratio, 3.95; P<0.001). Poor clinical outcomes among patients with low Dicer expression were validated in additional cohorts of patients. Rare missense mutations were found in the Dicer and Drosha genes, but their presence or absence did not correlate with the level of expression. Functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low Dicer expression. Conclusions Our findings indicate that levels of Dicer and Drosha mRNA in ovarian-cancer cells have associations with outcomes in patients with ovarian cancer.

Subfields: Cancer Research, Cell Biology, Plant Science

View Paper: https://www.semanticscholar.org/paper/003c0775b5de7d7b0bbd937a313406f5708248d9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

In Cell Biology

In Plant Science

Citations in the corpus

miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis (2020, background): “A decrease in the levels of these enzymes has been reported in the case of bladder [120] and ovarian cancers [121], while elevated levels are encountered in gastric [122] and cervical squamous cell neoplasms [123].”
A census of human RNA-binding proteins (2014, background): “7 Diseases of microRNA pathway components Mutations in miRNA-binding proteins are found in different cancers and developmental disorders (Kaneko et al., 2011; Merritt et al., 2008; Perron and Provost, 2009).”
A MicroRNA targeting dicer for metastasis control. (2010, background): “Genetically, as revealed by knockout of Dicer or Drosha in mice, miRNA biosynthesis is essential for basic cellular functions, such as stemness, cell-cycle progression, and mitosis (Bernstein et al., 2003; Fukagawa et al., 2004; Tang et al., 2007); these processes are ostensibly essential at all…”
MicroRNAs in development and disease. (2011, background): “The consensus, though, is that low Dicer expression in epithelial and serous ovarian cancer is associated with advanced tumor stage and low survival (169, 420).”
The mammalian ovary from genesis to revelation. (2009, background): “Lower mRNA and protein levels of DROSHA and DICER in advanced-stage, poorly differentiated epithelial ovarian carcinomas compared with benign OSE specimens have been reported (686).”
MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review (2012, neutral): “…loss of Dicer and/or Drosha has also been inversely correlated with outcome in lung cancer (Karube et al, 2005), cancers of the ovarian epithelium (Merritt et al, 2008), and more recently in other tumour types as nasopharyngeal carcinoma (Guo et al, 2012), neuroblastoma (Lin et al, 2010) and…”
Genetic variation in microRNA networks: the implications for cancer research (2010, neutral): “Low levels of DROSHA, for example, are associated with poor cancer surviva”
RNA interference in the clinic: challenges and future directions (2010, background): “We have shown that cancers can have altered levels of Drosha and Dicer, affecting the processing of precursors of siRNA such as short hairpin RNA”
microRNAs in cancer (2013, background): “For instance, decreases of 60% and 51% in the levels of Dicer and Drosha mRNAs, respectively, have been identified in 39% of patients with ovarian cancer (83).”