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Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain.

Authors
  • Bali, Kiran Kumar1
  • Selvaraj, Deepitha
  • Satagopam, Venkata P
  • Lu, Jianning
  • Schneider, Reinhard
  • Kuner, Rohini
  • 1 Medical Faculty Heidelberg, Institute for Pharmacology, Heidelberg University, Heidelberg, Germany; Molecular Medicine Partnership Unit with European Molecular Biology Laboratory, Heidelberg, Germany. , (Germany)
Type
Published Article
Journal
EMBO Molecular Medicine
Publisher
EMBO
Publication Date
November 2013
Volume
5
Issue
11
Pages
1740–1758
Identifiers
DOI: 10.1002/emmm.201302797
PMID: 24039159
Source
Medline
Keywords
License
Unknown

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.

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