MiR-672-5p-Mediated Upregulation of REEP6 in Spinal Dorsal Horn Participates in Bortezomib-Induced Neuropathic Pain in Rats.

Evidence shows that miRNAs are deeply involved in nervous system diseases, but whether miRNAs contribute to the bortezomib (BTZ)-induced neuropathic pain remains unclear. We aimed to investigate whether miRNAs contribute to bortezomib (BTZ)-induced neuropathic pain and explore the related downstream cascades. The level of miRNAs in the spinal dorsal horn was explored using miRNA microarray and PCR. MiR-672-5p was significantly downregulated in dorsal horn neurons in the rats with BTZ treatment. Intrathecal injection of miR-672-5p agomir blunted the increase of the amplitude and frequency of sEPSCs in dorsal horn neurons and mechanical allodynia induced by BTZ. In addition, the knockdown of miR-672-5p by intrathecal injection of antagomir increased the amplitude and frequency of sEPSCs in dorsal horn neurons and decreased the mechanical withdrawal threshold in naïve rats. Furthermore, silico analysis and the data from subsequent assays indicated that REEP6, a potential miR-672-5p-regulating molecule, was increased in the spinal dorsal horn of rats with BTZ-induced neuropathic pain. Blocking REEP6 alleviated the mechanical pain behavior induced by BTZ, whereas overexpressing REEP6 induced pain hypersensitivity in naïve rats. Importantly, we further found that miR-672-5p was expressed in the REEP6-positive cells, and overexpression or knockdown of miR-672-5p reversely regulated the REEP6 expression. Bioinformatics analysis and double-luciferase reporter assay showed the existence of interaction sites between REEP6 mRNA and miR-672-5p. Overall, our study demonstrated that miR-672-5p directly regulated the expression of REEP6, which participated in the neuronal hyperexcitability in the spinal dorsal horn and neuropathic pain following BTZ treatment. This signaling pathway may potentially serve as a novel therapeutic avenue for chemotherapeutic-induced mechanical hypersensitivity.

A new miRNA regulator, miR-672, reduces cardiac hypertrophy by inhibiting JUN expression.

Cardiac hypertrophy is one of the initial symptoms of many heart diseases. We found that miR-672-5p may participate in the regulation of heart disease development in mouse, but the association between miR-672-5p and cardiac hypertrophy remains unclear. In the present study, we found that the abundance of miR-672-5p decreased in hypertrophic cardiomyocytes induced by phenylephrine, angiotensin II (Ang II) and insulin-like growth factor 1. Putative target genes of miR-672-5p were identified using four pipelines, miRWalk, miRanda, RNA22 and Targetscan, and a total of 834 genes were predicted by all four pipelines. Among these target genes, 98 were associated with the development of heart disease. PPI networks showed that the Jun proto-oncogene product (JUN), a subunit of the AP-1 transcription factor, had the highest node degree, and it was defined as the hub gene of the PPI networks. Luciferase assays showed that miR-672-5p bound to the 3' UTR of the JUN gene and decreased luciferase activity, indicating that JUN is a target of miR-672-5p. Finally, we found that increasing the abundance of miR-672-5p in cardiomyocytes controlled the relative cell area in Ang II-stimulated hypertrophic cardiomyocytes. Correspondingly, the abundance of JUN, a target of miR-672-5p, was decreased in hypertrophic cardiomyocytes on both mRNA and protein levels, implying that miR-672-5p had suppressive effects on cardiac hypertrophy through regulating the expression of Jun in cardiomyocytes.