Profiling of miRnome in multiple myeloma

Abstract

Networking of miRNAs and their targets play a crucial regulatory role during disease pathogenesis and response to treatment in a wide variety of diseases including multiple myeloma (MM) and its subgroups. We have evaluated miRNA expression arrays (8x160K) as well as gene expression arrays (8x160K) (Agilent Technologies) among CD138 positive cells from MM patients (n=44) and 4 controls (Pooled from 10 Hodgkin's disease samples). The MM patients were classified as hyperdiploid (n=20) or non-hyperdiploid (n=24) based on aCGH profiles (Agilent technologies). Differentially expressed miRNAs (DEMs) were identified and their targets were predicted with Targetscan, Pictar and Tarbase analytical tools followed by their involvement in pathway network interactions. Extensive analyses revealed ∼ 98 significantly deregulated miRNAs including miR193b, miR10, miR15a, miR15b, miR17, miR18a, miR18b, miR29a, miR29b, miR29c, miR181a, miR181c and miR185 (FC ≥1.5, p≤0.05). The 284 gene targets of differentially expressed miRNAs as obtained from integration of miRNA and mRNA expression data included genes such as CD48, oncostatin M, E2F transcription factor 7 and IGF1. Further comparison of miRNA profiles of hyperdiploid Vs. non-hyperdiploid MM subgroups identified 67 miRNAs that were differentially expressed (FC ≥1.5, p≤0.05). The top 10 downregulated miRNAs included miR365a, miR221, miR30d, miR1246, miR29c, miR17, miR138 and miR181b, all of which are reported to be involved either in MM or other malignant conditions. An integrated analysis of miRNA and mRNA expression among hyperdiploid Vs. non-hyperdiploid identified 25 differentially regulated genes as potential targets of differentially expressed miRNAs. These included genes such as CYP1B1 (tumor antigen), MKI67 (proliferation related gene); TAF1 (transcription factor), RBL1 (senescence regulating gene), CTGF (angiogenic factor), and BCL2L10 (antiapototic gene). Identification of miRnome including miRNA and their targets that are deregulated could help understand disease pathology and design of possible therapeutic modalities.