Abstract
MicroRNAs play critical roles in regulating various physiological processes, including growth and development. Previous studies have shown that microRNA-124 (miR-124) participates not only in regulation of early neurogenesis but also in suppression of tumorigenesis. In the present study, we found that overexpression of miR-124 was associated with reduced DNA repair capacity in cultured cancer cells and increased sensitivity of cells to DNA-damaging anti-tumor drugs, specifically those that cause the formation of DNA strand-breaks (SBs). We then examined which DNA repair–related genes, particularly the genes of SB repair, were regulated by miR-124. Two SB repair–related genes, encoding ATM interactor (ATMIN) and poly (ADP-ribose) polymerase 1 (PARP1), were strongly affected by miR-124 overexpression, by binding of miR-124 to the 3¢-untranslated region of their mRNAs. As a result, the capacity of cells to repair DNA SBs, such as those resulting from homologous recombination, was significantly reduced upon miR-124 overexpression. A particularly important therapeutic implication of this finding is that overexpression of miR-124 enhanced cell sensitivity to multiple DNA-damaging agents via ATMIN- and PARP1-mediated mechanisms. The translational relevance of this role of miR-124 in anti-tumor drug sensitivity is suggested by the finding that increased miR-124 expression correlates with better breast cancer prognosis, specifically in patients receiving chemotherapy. These findings suggest that miR-124 could potentially be used as a therapeutic agent to improve the efficacy of chemotherapy with DNA-damaging agents.
Highlights
MicroRNAs are noncoding small RNAs that contribute to the regulation of their cognate target genes, usually by imperfect base-pairing with the 30-untranslated region (UTR) of the target mRNA, which results in cleavage/degradation of the mRNA and translational repression [1]
The effect of miR-124 seemed to be specific to the type of damage because we did not observe any differences between the miR-124overexpressing and vector control groups in the TMZ or 5-FU treatments (Fig 2A)
Restoration of ataxia telangiectasia mutated (ATM) interactor (ATMIN) and poly (ADP-ribose) polymerase 1 (PARP1) expression reverses the DNA repair defect induced by miR-124 overexpression and increases resistance to anti-tumor drugs
Summary
MicroRNAs are noncoding small RNAs that contribute to the regulation of their cognate target genes, usually by imperfect base-pairing with the 30-untranslated region (UTR) of the target mRNA, which results in cleavage/degradation of the mRNA and translational repression [1]. Selected examples include (a) miR-124 modulates cell growth via regulating the expression of cyclindependent kinase 6 [6]; (b) miR-124 suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis [8]; (c) miR-124 suppresses invasion and migration of oral squamous cell carcinoma by downregulating ITGB1 expression [9]; (d) the expression of phosphoinositide 3-kinase catalytic subunit alpha can be suppressed by miR-124, resulting in suppression of PI3K/Akt pathway and proliferation of hepatocellular carcinoma [10]; (e) miR-124 affects proliferation and motility of cancer cells by repressing ROCK2 and EZH2 [11]; (f) miR-124 determines the epithelial phenotype of breast cancer cells, by targeting the epithelial–mesenchymal transition regulator Slug and increasing the expression of E-cadherin, a hallmark of epithelial cells [12] All these findings suggest that miR-124 plays a crucial role as tumor suppressor in different kinds of tumors. We examined the effects of modulating miR-124 expression on cellular responses to the drugs used in cancer chemotherapy
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