The Effect of MicroRNA-124 Overexpression on Anti-Tumor Drug Sensitivity

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.

[1]  Chen-Yang Shen,et al.  Functional variants at the 21q22.3 locus involved in breast cancer progression identified by screening of genome-wide estrogen response elements , 2014, Breast Cancer Research.

[2]  N. Kanu,et al.  UBR5-mediated ubiquitination of ATMIN is required for ionizing radiation-induced ATM signaling and function , 2014, Proceedings of the National Academy of Sciences.

[3]  Kun Wang,et al.  Methylation-mediated silencing of the miR-124 genes facilitates pancreatic cancer progression and metastasis by targeting Rac1 , 2014, Oncogene.

[4]  Chen-Yang Shen,et al.  A novel estrogen receptor-microRNA 190a-PAR-1-pathway regulates breast cancer progression, a finding initially suggested by genome-wide analysis of loci associated with lymph-node metastasis. , 2014, Human molecular genetics.

[5]  A. Jemal,et al.  Breast cancer statistics, 2013 , 2014, CA: a cancer journal for clinicians.

[6]  N. Curtin,et al.  Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. , 2013, Molecular aspects of medicine.

[7]  Lizhuang Yang,et al.  MiR-124 inhibits the growth of glioblastoma through the downregulation of SOS1. , 2013, Molecular medicine reports.

[8]  Ying Chi,et al.  MicroRNA-124 Suppresses Breast Cancer Cell Growth and Motility by Targeting CD151 , 2013, Cellular Physiology and Biochemistry.

[9]  Di Wu,et al.  miRCancer: a microRNA-cancer association database constructed by text mining on literature , 2013, Bioinform..

[10]  M. He,et al.  MiR-124 targets Slug to regulate epithelial–mesenchymal transition and metastasis of breast cancer , 2012, Carcinogenesis.

[11]  Zhao-Qi Wang,et al.  Competition between NBS1 and ATMIN controls ATM signaling pathway choice. , 2012, Cell reports.

[12]  Anton J. Enright,et al.  A Neuronal Transcriptome Response Involving Stress Pathways is Buffered by Neuronal microRNAs , 2012, Front. Neurosci..

[13]  C. Ling,et al.  MiR-124 suppresses cell proliferation in hepatocellular carcinoma by targeting PIK3CA. , 2012, Biochemical and biophysical research communications.

[14]  Kevin Struhl,et al.  An HNF4α-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis , 2011, Cell.

[15]  C. Croce,et al.  MicroRNAs in the pathogenesis of cancer. , 2011, Seminars in oncology.

[16]  X. Bian,et al.  The putative tumour suppressor microRNA-124 modulates hepatocellular carcinoma cell aggressiveness by repressing ROCK2 and EZH2 , 2011, Gut.

[17]  Fengtang Yang,et al.  ATMIN Is Required for Maintenance of Genomic Stability and Suppression of B Cell Lymphoma , 2011, Cancer cell.

[18]  Adam V Jones,et al.  MicroRNA‐124 suppresses oral squamous cell carcinoma motility by targeting ITGB1 , 2011, FEBS letters.

[19]  Kwan Yeung Wong,et al.  Epigenetic Inactivation of the miR-124-1 in Haematological Malignancies , 2010, PloS one.

[20]  Jorge S Reis-Filho,et al.  Triple-negative breast cancer. , 2010, The New England journal of medicine.

[21]  L. Giustini,et al.  Triple-Negative Breast Cancer: Current State of the Art , 2010, Tumori.

[22]  Jason I. Herschkowitz,et al.  Small players with big roles: microRNAs as targets to inhibit breast cancer progression. , 2010, Current drug targets.

[23]  R. Agami,et al.  Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer , 2010, Molecular Cancer.

[24]  P. Maccallum,et al.  A metadata approach for clinical data management in translational genomics studies in breast cancer , 2009, BMC Medical Genomics.

[25]  G. Ottaviani,et al.  The etiology of osteosarcoma. , 2009, Cancer treatment and research.

[26]  Shiaw-Yih Lin,et al.  DNA Damage Response Pathways in Tumor Suppression and Cancer Treatment , 2009, World Journal of Surgery.

[27]  Debra L Winkeljohn.  Triple-negative breast cancer. , 2008, Clinical journal of oncology nursing.

[28]  Samuel H. Wilson,et al.  Corrigendum to "DNA damage response protein ASCIZ links base excision repair with immunoglobulin gene conversion" [Biochem. Biophys. Res. Commun. 371 (2008) 225-229] (DOI: 10.1016/j.bbrc.2008.04.052) , 2008 .

[29]  Chen-Yang Shen,et al.  Chk2‐dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair , 2008, The EMBO journal.

[30]  N. Kanu,et al.  ATMINistrating ATM signaling , 2008 .

[31]  Martin M Matzuk,et al.  A bioinformatics tool for linking gene expression profiling results with public databases of microRNA target predictions. , 2008, RNA.

[32]  R. Vibhakar,et al.  Regulation of cyclin dependent kinase 6 by microRNA 124 in medulloblastoma , 2008, Journal of Neuro-Oncology.

[33]  Samuel H. Wilson,et al.  DNA damage response protein ASCIZ links base excision repair with immunoglobulin gene conversion. , 2008, Biochemical and biophysical research communications.

[34]  Claudia Petritsch,et al.  miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells , 2008 .

[35]  Thomas Helleday,et al.  DNA repair pathways as targets for cancer therapy , 2008, Nature Reviews Cancer.

[36]  Yuriy Gusev,et al.  Computational methods for analysis of cellular functions and pathways collectively targeted by differentially expressed microRNA. , 2008, Methods.

[37]  N. Kanu,et al.  ATMINistrating ATM signalling: regulation of ATM by ATMIN. , 2008, Cell cycle.

[38]  T. Maniatis,et al.  The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. , 2007, Molecular cell.

[39]  N. Kanu,et al.  ATMIN defines an NBS1‐independent pathway of ATM signalling , 2007, The EMBO journal.

[40]  K. Caldecott,et al.  Poly(ADP-Ribose) Polymerase 1 Accelerates Single-Strand Break Repair in Concert with Poly(ADP-Ribose) Glycohydrolase , 2007, Molecular and Cellular Biology.

[41]  M. Fraga,et al.  Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. , 2007, Cancer research.

[42]  Wen-Lin Kuo,et al.  A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. , 2006, Cancer cell.

[43]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[44]  N. Curtin,et al.  The Novel Poly(ADP-Ribose) Polymerase Inhibitor, AG14361, Sensitizes Cells to Topoisomerase I Poisons by Increasing the Persistence of DNA Strand Breaks , 2005, Clinical Cancer Research.

[45]  J. Heierhorst,et al.  ASCIZ regulates lesion‐specific Rad51 focus formation and apoptosis after methylating DNA damage , 2005, The EMBO journal.

[46]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[47]  N. Curtin,et al.  Novel Poly(ADP-ribose) Polymerase-1 Inhibitor, AG14361, Restores Sensitivity to Temozolomide in Mismatch Repair-Deficient Cells , 2004, Clinical Cancer Research.

[48]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[49]  K. Caldecott.  XRCC1 and DNA strand break repair. , 2003, DNA repair.

[50]  A. Jemal,et al.  Breast Cancer Statistics , 2013 .

[51]  L. Thompson,et al.  XRCC3 promotes homology-directed repair of DNA damage in mammalian cells. , 1999, Genes & development.