title: CREB-regulated transcription coactivator 1 enhances CREB-dependent gene expression in spinal cord to maintain the bone cancer pain in mice.
abstract: BACKGROUND
  cAMP response element binding protein (CREB)-dependent gene expression plays an important role in central sensitization. CREB-regulated transcription coactivator 1 (CRTC1) dramatically increases CREB-mediated transcriptional activity. Brain-derived neurotrophic factor, N-methyl-d-aspartate receptor subunit 2B, and miRNA-212/132, which are highly CREB responsive, function downstream from CREB/CRTC1 to mediate activity-dependent synaptic plasticity and in turn loops back to amplify CREB/CRTC1 signaling. This study aimed to investigate the role of spinal CRTC1 in the maintenance of bone cancer pain using an RNA interference method.
  
  
  RESULTS
  Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeNCrlVr mice to induce bone cancer pain. Western blotting was applied to examine the expression of spinal phospho-Ser133 CREB and CRTC1. We further investigated effects of repeated intrathecal administration with Adenoviruses expressing CRTC1-small interfering RNA (siRNA) on nociceptive behaviors and on the upregulation of CREB/CRTC1-target genes associated with bone cancer pain. Inoculation of osteosarcoma cells induced progressive mechanical allodynia and spontaneous pain, and resulted in upregulation of spinal p-CREB and CRTC1. Repeated intrathecal administration with Adenoviruses expressing CRTC1-siRNA attenuated bone cancer-evoked pain behaviors, and reduced CREB/CRTC1-target genes expression in spinal cord, including BDNF, NR2B, and miR-212/132.
  
  
  CONCLUSIONS
  Upregulation of CRTC1 enhancing CREB-dependent gene transcription in spinal cord may play an important role in bone cancer pain. Inhibition of spinal CRTC1 expression reduced bone cancer pain. Interruption to the positive feedback circuit between CREB/CRTC1 and its targets may contribute to the analgesic effects. These findings may provide further insight into the mechanisms and treatment of bone cancer pain.
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
authors.forename: Bailing
authors.initials: B
authors.lastname: Hou
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
authors.forename: Yu-E
authors.initials: YE
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China mazhengliang1964@163.com.
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing, China.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Gu
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D000072716:Cancer Pain / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006614:Hindlimb / Q000473:pathology; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate; D013116:Spinal Cord / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C519509:Crtc1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D035683:MicroRNAs; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors
keywords: Adenoviruse; Bone cancer pain; CREB-regulated transcription coactivator 1; RNA interference; cAMP response element binding protein