miRConnect 2.0: identification of oncogenic, antagonistic miRNA families in three human cancers

Abstract

BackgroundBased on their function in cancer micro(mi)RNAs are often grouped as either tumor suppressors or oncogenes. However, miRNAs regulate multiple tumor relevant signaling pathways raising the question whether two oncogenic miRNAs could be functional antagonists by promoting different steps in tumor progression. We recently developed a method to connect miRNAs to biological function by comparing miRNA and gene array expression data from the NCI60 cell lines without using miRNA target predictions (miRConnect).ResultsWe have now extended this analysis to three primary human cancers (ovarian cancer, glioblastoma multiforme, and kidney renal clear cell carcinoma) available at the Cancer Genome Atlas (TCGA), and have correlated the expression of the clustered miRNAs with 158 oncogenic signatures (miRConnect 2.0). We have identified functionally antagonistic groups of miRNAs. One group (the agonists), which contains many of the members of the miR-17 family, correlated with c-Myc induced genes and E2F gene signatures. A group that was directly antagonistic to the agonists in all three primary cancers contains miR-221 and miR-222. Since both miR-17 ~ 92 and miR-221/222 are considered to be oncogenic this points to a functional antagonism of different oncogenic miRNAs. Analysis of patient data revealed that in certain patients agonistic miRNAs predominated, whereas in other patients antagonists predominated. In glioblastoma a high ratio of miR-17 to miR-221/222 was predictive of better overall survival suggesting that high miR-221/222 expression is more adverse for patients than high miR-17 expression.ConclusionmiRConnect 2.0 is useful for identifying activities of miRNAs that are relevant to primary cancers. The new correlation data on miRNAs and mRNAs deregulated in three primary cancers are available at miRConnect.org

microRNAs are biomarkers of oncogenic human papillomavirus infections

“…3). These observations are consistent with our understanding that the expression of both the miR-106b/93/25 and miR-17-5p/18a/19a/20a/19b/92a clusters is suppressed by p53 through an indirect mechanism via inhibition of E2F1 expression (44,47,48). Their up-regulation can then be attributed to the abilities of the HR HPV E6 to destabilize p53 and of the viral E7 to target the pRB/p130 protein family, resulting in the release of E2F from suppressive transcriptional complexes.…”

“…We note that miR-25, miR-27a, miR-92a, and miR-378 are oncogenic miRNAs and miR-16, miR-22, miR-29, and miR-100 are tumor-suppressive miRNAs (39)(40)(41)(42) and that they are modulated by p53, E2F, and c-Myc (25,(43)(44)(45). Although miR-16, miR-25, and miR-92a from three different miRNA clusters and noncluster miR-378 all had increased expression, the expression of the miR106b/93/25 cluster produced from MCM7 transcript (46) appears to be the most sensitive to oncogenic HPV infection, with increased expression in each of the three miRNAs from this cluster in all assays (Table 1).…”

Recurrent DGCR8, DROSHA, and SIX Homeodomain Mutations in Favorable Histology Wilms Tumors

“…Recent studies have shown that DROSHA RNase IIIB mutations result in global impairment of miRNA processing, with specific impairment in tumor-suppressing miRNAs [Rakheja et al, 2014]. We demonstrate that miRNAPG mutations are associated with down-regulation of all members of the miR-200 family (miR-200a, -200b, -200c, -141, and -429), which are key regulators of MET [Hua et al, 2013]. Reduction of miR-200 results in a mesenchymal, highly motile, and aggressive phenotype of cancer cells [Ceppi et al, 2014; Park et al, 2008; Ceppi et al, 2010].…”

“…Tumors with only SIX1/2 mutations (lacking miRNAPG mutations) and tumors with copy number loss of the miRNAPG loci without concomitant miRNAPG mutations did not cluster with the mutant tumors. Cluster 4 is characterized by decreased expression of the entire miR-200 family (miR-200a, -200b, -141, and -429) and miR-181b, all of which are involved in MET and stem cell maintenance [Hua et al, 2013; Ceppi et al, 2010; Park et al, 2008; Ceppi and Peter, 2014]. Decreased expression of the miR-200 family is predicted to reduce MYC and E2F expression [Hua et al, 2013], as was observed in our GSEA analysis of the miRNAPG-mutant tumors.…”

“…Within the cytoplasm, DICER1 cleaves the pre-miRNA to form mature miRNAs [Winters et al, 2009]. Given the multitude of cellular pathways miRNAs are known to affect, combined with their interactions and feedback loops, the range of effects associated with miRNAPG mutations is likely to be heterogeneous and complex [Hua et al, 2013]. Impaired miRNA synthesis has been shown to accelerate oncogenic transformation by deregulating target oncogenes and globally reducing mature miRNA levels [Kumar et al, 2007].…”