MicroRNAs (miRNAs) are single-stranded RNAs of 19-25 nucleotides in length and play a crucial role in regulating gene expression though post-transcriptional gene silencing which leads to mRNA degradation or translational repression. Recently, miRNAs are increasingly implicated in regulating cancer initiation and progression.
Here, we first tried to understand the roles of miRNAs in the pathogenic progress of multiple myeloma (MM), a plasma cell malignancy. In profiling assay of miRNA expression in MM cell lines and CD138+ bone marrow plasma cells (PCs) from subjects with MM, monoclonal gammopathy of undetermined significance (MGUS), and normal donors, we identified overexpression of miR-21, miR-106b-25 cluster, miR- 181a and b in MM and MGUS samples with respect to healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17-92 cluster, were shown to down regulate expression of SOCS-1. We also identified p300-CBP-associated factor, a gene involved in p53 regulation, as a bona fide target of the miR-106b-25 cluster, miR-181a and b. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis.
Next, we investigated the role of miRNAs in the p53 regulatory loop in human cancers, especially, Mutiple Myeloma (MM) and Glioblastoma Multiforme (GBM).
In multiple myeloma (MM), we provide evidence that miR-192, 194, and 215, which are downregulated in a subset of newly diagnosed MMs, can be transcriptionally activated by p53 and then modulate MDM2 expression. Furthermore, ectopic re-expression of these miRNAs in MM cells increases the therapeutic action of MDM2 inhibitors in vitro and in vivo by enhancing their p53-activating effects. In addition, miR-192 and 215 target the IGF pathway, preventing enhanced migration of plasma cells into bone marrow.
On the other hand, in human Glioblastom (GBM) two miRNAs, miR-25 and -32, are identified as p53-repressed miRNAs via p53-dependent, negative regulation of their transcriptional regulators, E2F1 and MYC. In addition, they result in p53 accumulation by directly targeting MDM2 and TSC1, negative regulators of p53 and the mTOR pathway, respectively, leading to inhibition of cellular proliferation through cell cycle arrest. Significantly, overexpression of transfected miR-25 and-32 in GBM cells inhibited growth of the GBM cells in mouse brain in vivo.
Altogether, these results define microRNAs as positive regulators of p53 underscoring their role in tumorigenesis in MM and GBM.