MicroRNA: important player in the pathobiology of multiple myeloma

Abstract

Recent studies have revealed a pivotal role played by a class of small, noncoding RNAs, microRNA (miRNA), in multiple myeloma (MM), a plasma cell (PC) malignancy causing significant morbidity and mortality. Deregulated miRNA expression in patient's PCs and plasma has been associated with tumor progression, molecular subtypes, clinical staging, prognosis, and drug response in MM. A number of important oncogenic and tumor suppressor miRNAs have been discovered to regulate important genes and pathways such as p53 and IL6-JAK-STAT signaling. miRNAs may also form complex regulatory circuitry with genetic and epigenetic machineries, the deregulation of which could lead to malignant transformation and progression. The translational potential of miRNAs in the clinic is being increasingly recognized that they could represent novel biomarkers and therapeutic targets. This review comprehensively summarizes current progress in delineating the roles of miRNAs in MM pathobiology and management.

Figure 1

miRNA and IL6-STAT3 signaling in MM. miR-21 is upregulated upon adherence of MM cells to BMSCs. It can be directly induced by STAT3 and contribute to the oncogenic potential of STAT3. At the same time, miR-21 can indirectly induce STAT3 by targeting PIAS3, a STAT3 inhibitor, forming a positive feedback loop. miR-19 has been shown to promote STAT3 signalling by repressing SOCS1. miR-29b could demethylate SOCS1 by targeting DNMTs, leading to upregulation of SOCS1, and negatively regulates IL6-STAT3 signalling.

Figure 2

miRNA and p53 in MM. P53 can be directly targeted by miR-125b, miR-25, and miR-30d and indirectly targeted by miR-106b~25 cluster, miR-32, miR-181a which target PCAF, a positive regulator of p53. Upregulation of these miRNAs in MM were observed in multiple studies. On the other hand, p53 transcriptionally induces miRs-192, -194, and -215 which target MDM2 and miR-34a which target SIRT1. Both pathways lead to upregulation of p53, forming two positive feedback loops. Deregulation of these miRNAs leads to compromised p53 tumor suppressor pathway and favors oncogenesis.