ABSTRACT
Among deregulated microRNAs (miRs) in human malignancies, miR-221 has been widely investigated for its oncogenic role and as a promising biomarker. Moreover, recent evidence suggests miR-221 as a fine-tuner of chronic liver injury and inflammation-related events. Available information also supports the potential of miR-221 silencing as promising therapeutic intervention. In this systematic review, we selected papers from the principal databases (PubMed, MedLine, Medscape, ASCO, ESMO) between January 2012 and December 2020, using the keywords "miR-221" and the specific keywords related to the most important hematologic and solid malignancies, and some non-malignant diseases, to define and characterize deregulated miR-221 as a valuable therapeutic target in the modern vision of molecular medicine. We found a major role of miR-221 in this view.
ABSTRACT
Multiple myeloma (MM) is a hematologic malignancy characterized by high genomic instability. Here we provide evidence that hyper-activation of DNA ligase III (LIG3) is crucial for genomic instability and survival of MM cells. LIG3 mRNA expression in MM patients correlates with shorter survival and even increases with more advanced stage of disease. Knockdown of LIG3 impairs MM cells viability in vitro and in vivo, suggesting that neoplastic plasmacells are dependent on LIG3-driven repair. To investigate the mechanisms involved in LIG3 expression, we investigated the post-transcriptional regulation. We identified miR-22-3p as effective negative regulator of LIG3 in MM. Enforced expression of miR-22 in MM cells downregulated LIG3 protein, which in turn increased DNA damage inhibiting in vitro and in vivo cell growth. Taken together, our findings demonstrate that myeloma cells are addicted to LIG3, which can be effectively inhibited by miR-22, promoting a novel axis of genome stability regulation.
Subject(s)
Biomarkers, Tumor/metabolism , DNA Ligase ATP/metabolism , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Multiple Myeloma/pathology , Poly-ADP-Ribose Binding Proteins/metabolism , Apoptosis , Biomarkers, Tumor/genetics , Cell Proliferation , DNA Damage , DNA Ligase ATP/genetics , DNA Repair , Humans , Multiple Myeloma/enzymology , Multiple Myeloma/genetics , Poly-ADP-Ribose Binding Proteins/genetics , Prognosis , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: MicroRNAs (miRNAs) are short non-coding RNAs that are crucial players as post-transcriptional regulators of messenger RNAs (mRNAs). miRNA deregulation has been associated to the pathogenesis of several human malignancies, since they might potentially regulate relevant pathways involved in cancer onset and progression. Therefore, targeting the miRNA network could represent a promising therapeutic strategy for human cancer. Area covered: This review summarizes recent findings on miRNAs as therapeutics or therapeutic targets against multiple myeloma (MM) and its microenvironment, including the challenges to overcome in the next future for the clinical application of this innovative therapeutic approach. Expert commentary: The rising body of advanced preclinical evidence on the biological activity of miRNAs in the pathobiology of MM strongly supports the therapeutic potential of treatment for this still incurable disease. However, translation of this therapeutic strategy for MM patients requires the development of optimized delivery systems and efficient integration of 'omics' data with clinical evidence, to precisely identify MM patients who may benefit from a novel miRNA-based therapy.
