Genome-wide identification and functional analyses of microRNA signatures associated with cancer pain
Menée in silico et in vivo, cette étude identifie des micro-ARNs dont la dérégulation est associée à une hypersensibilité nociceptive induite par une tumeur
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 behavioral approaches in a clinically-relevant model of metastatic bone-cancer pain in mice, we now show that tumor-induced conditions are associated with a marked dysregulation of 57 miRNAs in sensory neurons corresponding to tumor-affected areas. By establishing protocols for interference with disease-induced miRNA dysregulation in peripheral sensory neurons in vivo, we functionally validate 6 dysregulated miRNAs as significant modulators of tumor-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 tumor-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.
EMBO Molecular Medicine , résumé, 2012