Protective effect of LNA-anti-miR-132 therapy on liver fibrosis in mice

Abstract

microRNAs (miRs) are small regulatory RNAs that are frequently deregulated in liver disease. Liver fibrosis is characterized by excessive scarring caused by chronic inflammatory processes. In this study, we determined the functional role of miR-132 using a locked nucleic acid (LNA)-anti-miR approach in liver fibrosis. A significant induction in miR-132 levels was found in mice treated with CCl 4 and in patients with fibrosis/ cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl 4 -induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, a SMA, MCP1, IL-1b, and Cox2 was found in LNA-anti-miR-132treated mice. CCl 4 treatment increased caspase 3 activity and extracellular vesicles (EVs) in control but not in anti-miR-132-treated mice. Inhibition of miR-132 was associated with augmentation of MMP12 in the liver and Kupffer cells. In vivo and in vitro studies suggest miR-132 targets SIRT1 and inflammatory genes. Using tumor cancer genome atlas data, an increase in miR-132 was found in hepatocellular carcinoma (HCC). Increased miR-132 levels were associated with fibrogenic genes, higher tumor grade and stage, and unfavorable survival in HCC patients. Therapeutic inhibition of miR-132 might be a new approach to alleviate liver fibrosis, and treatment efficacy can be monitored by observing EV shedding.

LNA-anti-miR-150 alleviates renal interstitial fibrosis by reducing pro-inflammatory M1/M2 macrophage polarization

“…Chemically modified oligonucleotide small interfering RNAs and anti-miRs have been used to block the actions of specific endogenous genes and miRNA (25). More recently, LNA-anti-miR-132 has reduced liver fibrosis in a mouse model (26) LNA-anti-miR-150 reduced the renal infiltration of macrophages and polarization of M1/M2 macrophages in renal interstitial fibrosis mice. Western blotting and immunohistochemical (IHC) staining of the renal expression of CD68 protein, a classic biomarker for total macrophages (A).…”

miR-132-3p Modulates DUSP9-Dependent p38/JNK Signaling Pathways to Enhance Inflammation in the Amnion Leading to Labor

“…Upregulation of extracellular vesicles-packaged miR-132-3p released from CS-treated Th17 cells was shown to induce osteocastogenesis via COX2 downregulation [48]. Recently, administering LNA-anti-miR-132 in mice has been shown to attenuate CCL 4 -induced inflammatory mediators IL-1β and COX2 to alleviate liver fibrosis [49]. These reports indicate that the regulation of COX2 by miR-132-3p appears to be dependent on cell context, which can be either suppressive or promotive.…”

miRNAs in Liver Cancer

“…Another miRNA-132, which possibly shares with miRNA-34 SIRT1 as a common target, is miRNA-132. This miRNA is elevated in the response to alcohol consumption, while in vivo and in vitro studies suggest miR-132 targets SIRT1, being increased in HCC cells and associated with unfavorable survival in HCC patients [87].…”