Abstract
Macrophages plays a vital role in the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), but the polarization of macrophages was not consistent in previous reports and the contribution of hepatocytes to macrophage polarization is not clear. Here, we show that in clinical NASH and HCC samples, impaired Dicer activity was common and correlated with increased M1-like macrophages. Mice with Dicer deletion in hepatocytes could induce macrophages M1 polarization either in the development of NASH under high fat diet feeding, or in the carcinogenesis of HCC after DEN treatment. In hepatic cells, Dicer deletion delivered distinct lipid profile and increased lipid oxidation. Mechanically, Dicer deletion caused declined miR-192-3p and increased IGF2 in hepatocytes. Restoring miR-192-3p could suppress IGF2 and inhibit macrophage infiltration in the liver tissue, as well as reduce the lipid de novo synthesis and peroxidation. Overall, our data highlights the central role of Dicer-associated miR-192-3p in the etiopathogenesis of macrophage M1 polarization in NASH and HCC.
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Funding
This work was supported by the National Natural Science Foundation (No. 81972259, 31471189), the National Science Fund for Distinguished Young Scholars (No. 81525020), and the discipline construction and support project (No. XKTJ-JD202006) and the Hospital Youth aid project (No. SDFEYQN1901) of Second Affiliated Hospital of Soochow University. This work was also supported by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
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YL and JL: study concept and design; CH, XL, YC, YZ, YY, QZ, HN, and WG: acquisition of data; YS, LS, and YL: analysis and interpretation of data; YL: drafting of the manuscript; CH and YL: statistical analysis; WG and LS: technical or material support; YL and JL: obtained funding.
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Hu, C., Li, X., Sui, Y. et al. Dicer deletion in hepatocytes promotes macrophages M1 polarization through dysregulated miR-192-3p/IGF2 in non-alcoholic steatohepatitis and hepatocellular carcinoma. Cancer Gene Ther 29, 1252–1262 (2022). https://doi.org/10.1038/s41417-022-00432-x
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DOI: https://doi.org/10.1038/s41417-022-00432-x