Abstract
Abstract Objective: We hypothesize that certain microRNA (miRNA)-mRNA interactions are associated with malignant transformation and progression of MM. To date, no integrated analysis has been performed to identify mechanistic interactions between miRNA-mRNA that may drive the malignant phenotype. Method: Total RNA was extracted from 24 specimens of biopsy proven human MM and 6 specimens of normal pleura. Paired global transcriptional profiles of miRNA and genes (mRNA) expression were generated using Illumina microarrays. To optimize detection of causal associations, Spearman correlations between miRNA and mRNA expression were calculated among MM samples. Correlation p-values were converted to false discovery rates (FDR q-values) to account for multiple comparisons; associations with q<=0.05 were considered significant. To better determine the genes of relevance for a given process, sets of genes whose expression levels negatively correlated with specific miRNAs were identified as likely direct targets of that miRNA. Gene Set Enrichment Analysis (GSEA) was used to find target gene sets that were significantly repressed or overexpressed in MM vs normal in the opposite direction to expression of the miRNA itself. Independent data sets were interrogated with GSEA to refine target gene sets whose behavior was consistent across the data and identify which were associated with patient survival. Associations of mRNA expression levels and disease-specific survival were evaluated by univariate Cox proportional hazard regression. Result: We found multiple miRNA (total = 16) showing negative correlation in expression to multiple genes, and having the opposite expression pattern in MM vs normal compared to their putative targets. We arrived at this total by assessing the association between gene expression and outcome (disease-specific survival), and retaining only miRNA whose targets were significant (q<0.05). An example: expression of miR-192 (highly expressed in lung cancer) negatively correlated with expression of 156 mRNA (FDR<0.05). This miRNA was expressed 4-fold more in MM (FDR<0.01), while its gene targets showed an opposite pattern, being repressed in MM (FDR<0.001 in independent data). Functional annotation of target genes showed that they were enriched for targets of the Polycomb complex gene Ezh2, and for genes that are downregulated by KRAS in lung cancer. High expression of the genes negatively-correlated with miR-192 associated with better overall survival in an independent dataset, indicating that high expression of this miRNA affects poorer patient outcomes. Conclusion: Integrated analysis of miRNA and mRNA expression profiles in MM revealed novel miRNA associated with MM and identified putative interactions that may underlie the malignant phenotype. These miRNA-mRNA are candidates for functional validation. miR-192 is a putative oncogenic miRNA in MM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1149. doi:10.1158/1538-7445.AM2011-1149
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