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 CCl4 and in patients with fibrosis/cirrhosis. Inhibition of miR-132 in mice with LNA-anti-miR-132 caused decreases in CCl4-induced fibrogenesis and inflammatory phenotype. An attenuation in collagen fibers, α SMA, MCP1, IL-1β, and Cox2 was found in LNA-anti-miR-132-treated mice. CCl4 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.
| Original language | English |
|---|---|
| Pages (from-to) | 155-167 |
| Number of pages | 13 |
| Journal | Molecular Therapy Nucleic Acids |
| Volume | 25 |
| DOIs | |
| Publication status | Published - Sept 3 2021 |
Bibliographical note
Publisher Copyright:© 2021 The Authors
Funding
The authors thank Dr. Victor Ambros for his valuable suggestions and Dr. Timea Csak for her assistance in animal experiments. This work was supported by startup funds to S.B. by the Department of Medicine, University of Massachusetts Medical School ; by grant AA020744 to G.S.; and by grants from the Columbia University Irving Medical Center , the Columbia University College of Dental Medicine , the Irving Institute for Clinical and Translational Research ( UL1 TR001873 ), and Herbert Irving Comprehensive Cancer Center Multi PI grant ( P30 CA013696 ) to F.M.H. G.S. reports being a paid consultant for Allergan, Alnylam, Arrow, Durcect Corporation, Generon, Glympse Bio, Terra Firma, Quest Diagnostics, Pandion Therapeutics, Surrozen, and Zomagen. G.S. has received grants from Gilead, Genfit, Intercept, Novartis, SignaBlok, and Shire; she also holds intellectual property rights with UpToDate. All other authors declare no competing interests. The authors thank Dr. Victor Ambros for his valuable suggestions and Dr. Timea Csak for her assistance in animal experiments. This work was supported by startup funds to S.B. by the Department of Medicine, University of Massachusetts Medical School; by grant AA020744 to G.S.; and by grants from the Columbia University Irving Medical Center, the Columbia University College of Dental Medicine, the Irving Institute for Clinical and Translational Research (UL1 TR001873), and Herbert Irving Comprehensive Cancer Center Multi PI grant (P30 CA013696) to F.M.H. F.M.H.: conceptualization, methodology, validation, investigation, formal analysis, writing, visualization, and funding acquisition. D.C.: investigation. A.T.: writing, review, and editing. G.S.: resources. S.B.: conceptualization, methodology, validation, investigation, formal analysis, visualization, writing, supervision, and funding acquisition. G.S. reports being a paid consultant for Allergan, Alnylam, Arrow, Durcect Corporation, Generon, Glympse Bio, Terra Firma, Quest Diagnostics, Pandion Therapeutics, Surrozen, and Zomagen. G.S. has received grants from Gilead, Genfit, Intercept, Novartis, SignaBlok, and Shire; she also holds intellectual property rights with UpToDate. All other authors declare no competing interests.
| Funders | Funder number |
|---|---|
| Alnylam | |
| Department of Medicine, University of Massachusetts Medical School | AA020744 |
| Gilead Sciences | |
| Institute for Clinical and Translational Research, University of Wisconsin, Madison | UL1 TR001873, P30 CA013696 |
| Allergan | |
| College of Dental Medicine, Columbia University | |
| Irving Medical Center, Columbia University | |
| Shire |
ASJC Scopus Subject Areas
- Molecular Medicine
- Drug Discovery
