Anti-mR-221–222 therapy, by increasing the level of PUMA, which is downstream of GR and p53, may abrogate drug resistance associated with p53 inactivation and decreased GR expression (Zhao et al., Cancer Research, 2015)
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Defining the role of miRs in the pathogenesis of multiple myeloma
A secondary focus of our laboratory is to investigate the role of miRs in the pathogenesis of MM. MiRs are small (~22nt) noncoding RNAs that negatively regulate protein-coding gene expression by targeting mRNA degradation or translation inhibition. Dysregulation of miR expression is frequently observed in human cancers including MM, and has been associated with progressive disease, metastasis, drug resistance, and poor clinical outcome suggesting an important role of miRs in tumor progression. MiRs can function as either tumor suppressors or oncogenes, and have aroused interest as potential developmental foci for cancer therapy. In our recent studies we have demonstrated that the miR-30-5p family is frequently downregulated in MM and functions as a tumor suppressor and novel therapeutic tool by targeting oncogenic Wnt/β-catenin/BCL9 pathway, in addition we have found that the miR-221-222 family is frequently overexpressed in MM and anti-miR-221-222 therapy abrogates dexamethasone resistance by targeting the PUMA/BAK/BAX pathway. These studies point for the first time to a key role of the miR-30-5p and miR-221-222 families in the pathogenesis of MM, and provide compelling proof-of-concept for the potential exploitation of their role in MM therapy. |