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Dicer deletion in hepatocytes promotes macrophages M1 polarization through dysregulated miR-192-3p/IGF2 in non-alcoholic steatohepatitis and hepatocellular carcinoma

Cancer Gene Therapy volume 29, pages 1252–1262 (2022)Cite this article

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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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Fig. 1: The expression of Dicer decreases in HCC and NASH.
Fig. 2: Dicer LKO mice develop NASH and HCC spontaneously with macrophages M1 polarization.
Fig. 3: Dicer LKO mice show macrophages M1 polarization and NASH under high fat diet.
Fig. 4: Dicer LKO mice are more susceptible to DEN-induced HCC with macrophages M1 polarization in the microenvironment.
Fig. 5: Dicer LKO mice show distinct lipid profile and increased lipid oxidation.
Fig. 6: Dicer deletion causes dysregulated miR-192-3p/IGF2 in hepatocytes.
Fig. 7: Over expression of miR-192-3p suppresses IGF2 and ameliorates NASH in Dicer LKO mice.

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All data in this study is available upon request.

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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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Author notes

  1. These authors contributed equally: Caihong Hu, Xiaoli Li, Yiqun Sui.

Authors and Affiliations

  1. Department of Pathology and Pathophysiology, Medical College of Soochow University, Suzhou, China

    Caihong Hu, Xiaoli Li, Yongyu Chen, Ying Zhao, Yan Yang, Qun Zhou, Hengli Ni, Lina Sun, Jianming Li & Yao Liu

  2. Department of Pathology, the Second Affiliated Hospital of Soochow University, Suzhou, China

    Yiqun Sui & Yao Liu

  3. Department of Pathology, Heze Municiple Hospital, Heze, China

    Qun Zhou

  4. Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

    Hengli Ni & Jianming Li

  5. Department of Pathology, the First Affiliated Hospital of Soochow University, Suzhou, China

    Wenjuan Gan

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  1. Caihong Hu
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Contributions

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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Correspondence to Jianming Li or Yao Liu.

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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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