The epigenetic regulation of the opioid system: new individualized prompt prevention and treatment strategies.

The most well-known physiological effect associated with opiod system is their efficacy in pain reduction or analgesia, although their effect on a variety of other physiological and physiophological functions has become apparent in recent years. This review is an attempt to clarify in more detail the epigenetic regulation of opioid system to understand with more precision their transcriptional and posttranscriptional regulation in multiple pyisiological and pharmacological contexts. The opioid receptors show an epigenetic regulation and opioid peptide precursors by methylation, chromatin remodeling and microRNA. Although the opioid receptor promoters have similarity between them, they use different epigenetic regulation forms and they exhibit different pattern of expression during the cell differentiation. DNA methylation is also confirmed in opioid peptide precursors, being important for gene expression and tissue specificity. Understanding the epigenetic basis of those physiological and physiopathological procesess is essential for the development of individualized prompt prevention and treatment strategies.

RKIP Regulates Differentiation-Related Features in Melanocytic Cells.

Raf Kinase Inhibitor Protein (RKIP) has been extensively reported as an inhibitor of key signaling pathways involved in the aggressive tumor phenotype and shows decreased expression in several types of cancers. However, little is known about RKIP in melanoma or regarding its function in normal cells. We examined the role of RKIP in both primary melanocytes and malignant melanoma cells and evaluated its diagnostic and prognostic value. IHC analysis revealed a significantly higher expression of RKIP in nevi compared with early-stage (stage I-II, AJCC 8th) melanoma biopsies. Proliferation, wound healing, and collagen-coated transwell assays uncovered the implication of RKIP on the motility but not on the proliferative capacity of melanoma cells as RKIP protein levels were inversely correlated with the migration capacity of both primary and metastatic melanoma cells but did not alter other parameters. As shown by RNA sequencing, endogenous RKIP knockdown in primary melanocytes triggered the deregulation of cellular differentiation-related processes, including genes (i.e., ZEB1, THY-1) closely related to the EMT. Interestingly, NANOG was identified as a putative transcriptional regulator of many of the deregulated genes, and RKIP was able to decrease the activation of the NANOG promoter. As a whole, our data support the utility of RKIP as a diagnostic marker for early-stage melanomas. In addition, these findings indicate its participation in the maintenance of a differentiated state of melanocytic cells by modulating genes intimately linked to the cellular motility and explain the progressive decrease of RKIP often described in tumors.