An integrative genomic approach reveals coordinated expression of intronic miR-335, miR-342, and miR-561 with deregulated host genes in multiple myeloma

Background: The role of microRNAs (miRNAs) in multiple myeloma (MM) has yet to be fully elucidated. To miRNAs that are potentially deregulated in MM, we investigated those mapping within transcription units, based evidence that intronic miRNAs are frequently coexpressed with their host genes. To this end, we monitored transcript expression values in a panel of 20 human MM cell lines (HMCLs) and focused on transcripts whose varied significantly across the dataset. Methods: miRNA expression was quantified by Quantitative Real-Time PCR. Gene expression and genome data were generated on Affymetrix oligonucleotide microarrays. Significant Analysis of Microarrays algorithm was to investigate differentially expressed transcripts. Conventional statistics were used to test correlations for Public libraries were queried to predict putative miRNA targets. Results: We identified transcripts specific to six miRNA host genes (CCPG1, GULP1, EVL, TACSTD1, MEST, and TNK) whose average changes in expression varied at least 2-fold from the mean of the examined dataset. We evaluated expression levels of the corresponding intronic miRNAs and identified a significant correlation between the levels of MEST, EVL, and GULP1 and those of the corresponding miRNAs miR-335, miR-342-3p, and miR-561 respectively. Genome-wide profiling of the 20 HMCLs indicated that the increased expression of the three host and their corresponding intronic miRNAs was not correlated with local copy number variations. Notably, miRNAs their host genes were overexpressed in a fraction of primary tumors with respect to normal plasma cells; however, finding was not correlated with known molecular myeloma groups. The predicted putative miRNA targets and transcriptional profiles associated with the primary tumors suggest that MEST/miR-335 and EVL/miR-342-3p may play role in plasma cell homing and/or interactions with the bone marrow microenvironment. Conclusion: Our data support the idea that intronic miRNAs and their host genes are regulated dependently, and contribute to the understanding of their biological roles in cancer. To our knowledge, this is the first evidence deregulated miRNA expression in MM, providing insights that may lead to the identification of new biomarkers altered molecular pathways of the disease.