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.

Epigenetic Modification of Spinal miR-219 Expression Regulates Chronic Inflammation Pain by Targeting CaMKIIγ

“…Conditional deletion of Dicer, a central enzyme in miRNA processing, in DRG sensory neurons leads to deficits in inflammatory pain (Zhao et al, 2010). miRNA expression profiling study in DRG tissue identified 63 and 57 miRNAs whose expression is significantly altered after neuropathic pain (von Schack et al, 2011) and metastatic bone-cancer pain model (Bali et al, 2013). Furthermore, upregulation of spinal miR-124 or miR-103 is reported to prevent and treat persistent inflammatory and neuropathic pain (Favereaux et al, 2011;Willemen et al, 2012).…”

“…Inhibiting the tumor-induced upregulation of miR-146a and miR-183 in sensory neurons markedly attenuates tumor-mediated hyperalgesia (Li et al, 2013). In contrast, augmenting the expression of miR-370 in DRGs leads to exaggerated tumor-mediated hyperalgesia (Bali et al, 2013). These findings demonstrate miRNAs as key regulators of physiologic and pathologic processes underlying chronic pain and suggest that specific miRNAs may act as new molecular targets for pain prevention and relief.…”

“…Recently, several screening studies have shown dysregulated expression of miRNAs in pain pathways from primary afferent nociceptors, DRG, spinal cord, and brain areas associated with pain perception in different inflammatory, neuropathic, and cancer pain models. Manipulation of miRNA expression prevents and reverses persistent inflammatory, neuropathic, and cancer pain behavior (Favereaux et al, 2011;Imai et al, 2011;Bali et al, 2013). In addition, the functional consequences of miRNA regulation of downstream targets and intrinsic neuronal excitability have also been demonstrated.…”

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

“…It should be pointed out that the differences found across different pain models suggest the existence of disorder specific miRNAs rather than common miRNA regulators of nociceptive modulation. For example, members of the miR-34 family are strongly underexpressed following neuropathic pain induction while appears highly overexpressed following bone metastatic pain induction in DRG [85,86]. Also, it has been described that the interactions between sensory neurons and non-neuronal cells such as immune cells and microglia modulate nociceptive sensitivity [87] and therefore changes in other cells of the body, such as blood cells, might be indicators of individual changes in nociceptive thresholds, even if the alteration pattern of the deregulated microRNAs does not match with that in the tissue affected they might still serve as reporters.…”

Study of the analgesic activities, chronic toxicity and addictive potential of Jia-Yuan-Qing pill in rats

“…It has been reported that approximately one-third of patients who are actively receiving treatment for cancer, and two-thirds of those with advanced malignant disease experience pain (1). Cancer pain, particularly bone cancer pain, which is one of the most frequent symptoms in bone cancer patients (2), affects their quality of life, and current treatments are limited (3).…”