High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2

Abstract

MicroRNAs (miRNAs) are noncoding RNAs that regulate global gene expression. miRNAs often act synergistically to repress target genes, and their dysregulation can contribute to the initiation and progression of a variety of cancers. The clinical relationship between global expression of miRNA and mRNA in cancer has not been studied in detail. We used whole-genome microarray analyses of CD138-enriched plasma cells from 52 newly diagnosed cases of multiple myeloma to correlate miRNA expression profiles with a validated mRNA-based risk stratification score, proliferation index, and predefined gene sets. In stark contrast to mRNAs, we discovered that all tested miRNAs were significantly up-regulated in high-risk disease as defined by a validated 70-gene risk score (P < 0.01) and proliferation index (P < 0.05). Increased expression of EIF2C2/AGO2, a master regulator of the maturation and function of miRNAs and a component of the 70-gene mRNA risk model, is driven by DNA copy number gains in MM. Silencing of AGO2 dramatically decreased viability in MM cell lines. Genome-wide elevated expression of miRNAs in high-risk MM may be secondary to deregulation of AGO2 and the enzyme complexes that regulate miRNA maturation and function. DICER1 | expression profile | multiple myeloma | risk stratification | system biology M icroRNAs (miRNAs) belong to a class of noncoding small RNAs with mature sequences that contain ≈22 nucleotides (1). As repressors of gene expression, miRNAs can bind to the 3′ untranslated region (3′UTR) of an mRNA and inhibit its translation or induce its degradation (1).Dysregulation of miRNA is involved in cancer initiation and progression (2, 3), and miRNA expression profiles have prognostic implications (4-6). Inhibiting miRNA has proved effective in vivo (7) and therefore could be a novel therapeutic strategy for cancer (8, 9). To date, few studies have investigated the roles of miRNA in multiple myeloma (MM), a plasma cell dyscrasia that homes to and expands in the bone marrow and produces disease manifestations that include osteolytic bone destruction with hypercalcemia, anemia, immunosuppression, and end-organ damage (10). Several miRNAs have been implicated in survival and growth of myeloma cells and myeloma tumor growth. For instance, miR-21 is a target of Stat3 and thus a critical component in IL-6/Stat3-dependent survival and growth pathways of myeloma cells (11). In addition, IL-6 inhibitor SOCS1 and p53 pathway component p300-CBPassociated factor are targets of multiple miRNAs, including miR-106b-25 cluster, miR-32, miR-181a/b, and miR-19a/b (12); suppression of these miRNAs inhibited myeloma tumor growth in nude mice (12).Applying miRNA expression profiles, Pichiorri et al. (12) identified miRNAs that were differentially expressed in plasma cells of healthy donors, subjects with a benign precursor to MM (monoclonal gammopathy of undetermined significance), and patients with MM. In other miRNA expression profiling studies, Roccaro et al. (13) To further investigate the potential involvement o...

Argonaute2 promotes tumor metastasis by way of up-regulating focal adhesion kinase expression in hepatocellular carcinoma

“…The increased expression of Ago2, along with a gain in DNA copy number, was shown to correlate with highrisk myeloma, whereas Ago2 silencing induced by shRNA led to a decreased viability of myeloma cell lines. 20 Interestingly, in our study Ago2 overexpression promoted HCC tumorigenesis and progression, including tumor invasion and distant lung metastasis, which are supported by both in vitro and in vivo experiments. Conversely, Ago2 knockdown induced by RNAi inhibited cell metastasis (Figs.…”

“…19 Ago2 overexpression was involved in high-risk myeloma by way of elevating global miRNAs. 20 Moreover, the elevated Ago2 expression could raise the possibility that it augments tumorigenic potential in breast cancer by enhancing miRNA activity. 21 It has also been reported that Ago2 knockdown induced apoptosis in myeloid leukemia cells and inhibited siRNA-mediated silencing of transfected oncogenes in HEK-293 cells.…”

MiR-125 in normal and malignant hematopoiesis

“…A few cases of MM were found to express miR-125b-2, in particular the translocation/cyclin classification #5, involving either the t(14;16)(q32;q23) or t(14;20)(q32;q11) translocations (up to 14-fold upregulation) 50,51 (Table 1). Interestingly, similar to ALL, miR-125b-2 is not overexpressed in MM with trisomy 21.…”

“…48 Moreover, it is hardly expressed in ALL or myelomas with somatic trisomy 21. 48,50,51 Thus, there is no correlation between the expression of miR-125b and its genomic copy.…”

Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication

“…Moreover, several miRNA have been involved in the pathogenesis of multiple myeloma (MM). [1][2][3] In this sense, it has recently been shown that there is a mechanism of p53 regulation through miRNA acting on MDM2 expression; thus, miR-192, 194 and 215 re-expression in myeloma cell lines induced degradation of MDM2 with subsequent p53 up-regulation and cell growth inhibition. 4 In addition, miR-15a and 16 have also been shown to regulate myeloma proliferation by inhibiting AKT and MAP-kinases, and by reducing bone marrow angiogenesis.…”