title: Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.
abstract: Cancer pain remains a major challenge and there is an urgent demand for the development of specific mechanism-based therapies. Various diseases are associated with unique signatures of expression of microRNAs (miRNAs), which reveal deep insights into disease pathology. Using a comprehensive approach combining genome-wide miRNA screening, molecular and in silico analyses with behavioural approaches in a clinically relevant model of metastatic bone-cancer pain in mice, we now show that tumour-induced conditions are associated with a marked dysregulation of 57 miRNAs in sensory neurons corresponding to tumour-affected areas. By establishing protocols for interference with disease-induced miRNA dysregulation in peripheral sensory neurons in vivo, we functionally validate six dysregulated miRNAs as significant modulators of tumour-associated hypersensitivity. In silico analyses revealed that their predicted targets include key pain-related genes and we identified Clcn3, a gene encoding a chloride channel, as a key miRNA target in sensory neurons, which is functionally important in tumour-induced nociceptive hypersensitivity in vivo. Our results provide new insights into endogenous gene regulatory mechanisms in cancer pain and open up attractive and viable therapeutic options.
authors.affiliation: Medical Faculty Heidelberg, Institute for Pharmacology, Heidelberg University, Heidelberg, Germany; Molecular Medicine Partnership Unit with European Molecular Biology Laboratory, Heidelberg, Germany.
authors.forename: Kiran Kumar
authors.initials: KK
authors.lastname: Bali
authors.forename: Deepitha
authors.initials: D
authors.lastname: Selvaraj
authors.forename: Venkata P
authors.initials: VP
authors.lastname: Satagopam
authors.forename: Jianning
authors.initials: J
authors.lastname: Lu
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneider
authors.forename: Rohini
authors.initials: R
authors.lastname: Kuner
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D051379:Mice; D008809:Mice, Inbred C3H; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D010146:Pain / Q000235:genetics* / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism
chemical_list: D035683:MicroRNAs
keywords: Clcn3; bone metastatic pain; gene regulation; miRNA inhibitors; miRNA mimics
references.citation: Biochem Biophys Res Commun. 2010 Apr 9;394(3):792-7
references.pmid: 20230787
references.citation: Mol Pain. 2011 Sep 27;7:73
references.pmid: 21951917
references.citation: Trends Genet. 2005 May;21(5):289-97
references.pmid: 15851066
references.citation: Nature. 2005 Dec 1;438(7068):685-9
references.pmid: 16258535
references.citation: Novartis Found Symp. 2004;261:194-214; discussion 214-9, 256-61
references.pmid: 15469052
references.citation: Oncology (Williston Park). 1999 May;13(5 Suppl 2):25-9
references.pmid: 10356695
references.citation: Nat Rev Neurosci. 2006 Oct;7(10):797-809
references.pmid: 16988655
references.citation: J Comput Biol. 2006 May;13(4):996-1003
references.pmid: 16761924
references.citation: Comput Biol Chem. 2006 Feb;30(1):21-6
references.pmid: 16321570
references.citation: Exp Neurol. 2012 Jun;235(2):402-18
references.pmid: 22245616
references.citation: Anesth Analg. 2003 Apr;96(4):1096-1103
references.pmid: 12651667
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17615-20
references.pmid: 23047694
references.citation: RNA. 2004 May;10(5):766-71
references.pmid: 15100431
references.citation: J Neurosci. 2001 Dec 1;21(23):9367-76
references.pmid: 11717370
references.citation: Histochem Cell Biol. 2011 Jan;135(1):37-45
references.pmid: 21170745
references.citation: PLoS Biol. 2012;10(3):e1001283
references.pmid: 22427743
references.citation: PLoS One. 2011 Mar 14;6(3):e17670
references.pmid: 21423802
references.citation: J Neurosci. 2011 Jun 1;31(22):8134-42
references.pmid: 21632935
references.citation: Adv Pharmacol. 2006;54:1-27
references.pmid: 17175808
references.citation: J Neurosci. 2010 Aug 11;30(32):10860-71
references.pmid: 20702715
references.citation: J Neurosci. 2008 May 7;28(19):5072-81
references.pmid: 18463260
references.citation: J Biol Chem. 2010 Apr 9;285(15):11188-96
references.pmid: 20139089
references.citation: Neuron. 2006 Feb 2;49(3):365-77
references.pmid: 16446141
references.citation: Pain. 2011 Mar;152(3):649-655
references.pmid: 21239111
references.citation: Am J Physiol Cell Physiol. 2008 Jan;294(1):C251-62
references.pmid: 17977943
references.citation: Cell. 2007 Apr 20;129(2):247-9
references.pmid: 17448987
references.citation: Nat Rev Drug Discov. 2009 Feb;8(2):129-38
references.pmid: 19180106
references.citation: Mol Pain. 2008 Apr 01;4:11
references.pmid: 18377664
references.citation: Curr Opin Support Palliat Care. 2007 Apr;1(1):6-10
references.pmid: 18660717
references.citation: Am J Respir Crit Care Med. 2012 Feb 15;185(4):409-19
references.pmid: 22161164
references.citation: Neuroscience. 2009 Dec 1;164(2):711-23
references.pmid: 19699278
references.citation: EMBO J. 2011 Jul 29;30(18):3830-41
references.pmid: 21804529
references.citation: Nat Med. 2009 Jul;15(7):802-7
references.pmid: 19525966
references.citation: Mol Pain. 2007 Jun 08;3:15
references.pmid: 17559665
references.citation: Oncogene. 2013 Mar 21;32(12):1530-8
references.pmid: 22580603
references.citation: Mol Cancer. 2012 Aug 17;11:56
references.pmid: 22900969
references.citation: Nucleic Acids Res. 2007;35(9):2885-92
references.pmid: 17439965
references.citation: EMBO J. 2011 Sep 23;30(20):4299-308
references.pmid: 21946562
references.citation: J Neurosci. 2011 Oct 26;31(43):15294-9
references.pmid: 22031875
references.citation: Neuroscience. 2008 Aug 13;155(2):510-21
references.pmid: 18616987
references.citation: Gene. 2011 Jul 1;480(1-2):34-41
references.pmid: 21397669
references.citation: Eur J Pain. 2011 Sep;15(8):801.e1-12
references.pmid: 21397537
references.citation: Neurosci Res. 2006 May;55(1):1-10
references.pmid: 16516994
references.citation: J Neurosci. 2001 Dec 1;21(23):9355-66
references.pmid: 11717369
references.citation: Am J Physiol Cell Physiol. 2008 Feb;294(2):C535-42
references.pmid: 18077605
references.citation: J Neurosci. 2011 Oct 5;31(40):14191-203
references.pmid: 21976504
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22296-301
references.pmid: 21135246
references.citation: Science. 2008 Aug 1;321(5889):702-5
references.pmid: 18669863
references.citation: Brain Res. 2007 Jul 30;1160:102-12
references.pmid: 17588550
references.citation: Brain. 2010 Sep;133(9):2515-8
references.pmid: 20802201
references.citation: Mol Pain. 2011 Mar 07;7:17
references.pmid: 21385380
references.citation: J Biol Chem. 2012 Feb 17;287(8):6002-13
references.pmid: 22187436
references.citation: Oncogene. 2013 Jan 24;32(4):414-21
references.pmid: 22391569
references.citation: Int J Med Sci. 2010 Aug 02;7(5):251-9
references.pmid: 20714435
references.citation: Artif DNA PNA XNA. 2010 Jul;1(1):36-44
references.pmid: 21687525
references.citation: Nat Rev Genet. 2004 Apr;5(4):316-23
references.pmid: 15131654
references.citation: Nat Rev Genet. 2006 Jun;7(6):475-82
references.pmid: 16622413
references.citation: Nature. 2008 Jan 17;451(7176):330-4
references.pmid: 18202657
references.citation: Pain. 2008 May;136(1-2):188-201
references.pmid: 18316160
references.citation: Nat Med. 2004 Jul;10(7):712-8
references.pmid: 15195086
references.citation: Mol Pharmacol. 1999 Oct;56(4):807-12
references.pmid: 10496965
references.citation: Bioinformatics. 2003 Jan 22;19(2):185-93
references.pmid: 12538238
references.citation: Pain. 2012 Mar;153(3):710-721
references.pmid: 22296735
references.citation: J Biol Chem. 2001 Jun 8;276(23):20093-100
references.pmid: 11274166
references.citation: Pain. 2007 Jan;127(1-2):17-26
references.pmid: 16965855