title: Positive feedback regulation between microRNA-132 and CREB in spinal cord contributes to bone cancer pain in mice.
abstract: cAMP response element-binding protein (CREB)-dependent gene expression plays an important role in central sensitization. CREB-regulated transcription coactivator 1 (CRTC1) dramatically increase CREB-mediated transcriptional activity. microRNA-132 (miR-132), which is highly CREB-responsive, functions downstream from CREB/CRTC1 to mediate activity-dependent synaptic plasticity and in turn loops back to amplify CREB/CRTC1 signalling. This study aimed to investigate the positive feedback regulation between miR-132 and CREB in spinal cord in the maintenance of bone cancer pain.
  
  
  
  Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeNCrlVr mice to induce bone cancer pain. We further investigated effects of repeated intrathecal administration with Adenoviruses expressing CREB-siRNA or miR-132 antisense locked nucleic acid (LNA), respectively, on nociceptive behaviours and on the activity of CREB/CRTC1 signalling.
  
  
  
  Intramedullary inoculation of osteosarcoma cells resulted in up-regulation of spinal p-CREB, CRTC1 and CREB-target genes (NR2B and miR-132). Repeated intrathecal administration with Adenoviruses expressing CREB-siRNA or miR-132 LNA-AS, respectively, attenuated bone cancer-evoked pain behaviours, reduced the activity of CREB/CRTC1 signalling and down-regulated CREB-target gene NR2B expression in spinal cord.
  
  
  
  These findings suggest that activation of spinal CREB/CRTC1 signalling may play an important role in bone cancer pain. Interruption to the positive feedback regulation between CREB/CRTC1 and its target gene miR-132 can effectively relieved the bone cancer-induced mechanical allodynia and spontaneous pain. WHAT DOES THIS STUDY ADD?: The positive feedback regulation between CREB/CRTC1 and its target gene miR-132 in spinal cord plays an important role in bone cancer pain.
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu province, China.
authors.forename: B
authors.initials: B
authors.lastname: Hou
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu province, China.
authors.forename: X
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu province, China.
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu province, China.
authors.forename: M
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu province, China.
authors.forename: Y E
authors.initials: YE
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu province, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, Jiangsu province, China.
authors.forename: X
authors.initials: X
authors.lastname: Gu
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism*; D000072716:Cancer Pain / Q000209:etiology* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D035683:MicroRNAs / Q000378:metabolism*; D012516:Osteosarcoma / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C519509:Crtc1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C546976:MIRN132 microRNA, mouse; D035683:MicroRNAs; D014157:Transcription Factors