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