Journal Article

Deletion of Tfap2a in hepatocytes and macrophages promotes the progression of hepatocellular carcinoma by regulating SREBP1/FASN/ACC pathway and anti-inflammatory effect of IL10

He, Jun, Li, Zhiwei, Zhang, Zixin, Huang, Guixiang, Hou, Anyi, Zhou, Hao, Hu, Xiang, Zhang, Chun, Qin, Yanling, Wang, Qinghao, Ding, Xiaofeng, Liu, Xiran, Li, Limin

2025

Overview

The transcription factor AP-2α plays a crucial role in the control of tumor development and progression, and suppresses the proliferation and migration of hepatocellular carcinoma (HCC). However, the detailed function and mechanisms of AP-2α in the pathogenesis of HCC are still elusive. In the current study, we investigated the role of AP-2α regulation in liver injury-mediated HCC development. Downregulation of Tfap2a expression was found in the livers of DEN/CCl 4 -induced fibrosis and HCC mouse model. Hepatocyte (Alb-Cre), hepatic stellate cell (HSC) (Lrat-Cre) and macrophage (LysM-Cre) specific Tfap2a knockout mice were generated, respectively. Conditional knockout of Tfap2a was able to promote hepatic steatosis in Tfap2a ΔHep and Tfap2a ΔMΦ mice, but not in Tfap2a ΔHSC mice fed with normal chow. Tfap2a ΔHep and Tfap2a ΔMΦ mice treated with DEN/CCl 4 for 6 months increased tumor burden compared to Tfap2a flox controls. Tfap2a-deleted macrophages or hepatocytes could enhance lipid droplet (LD) accumulation in hepatocytes. Mechanistically, AP-2α binds to the promoter regions of SREBP1/ACC/FASN and inhibits hepatic lipid de novo synthesis. Deletion of Tfap2a in macrophages enhances polarization of M1 macrophages with increased iNOS expression but decreased CD206 expression, which resulted in increased pro-inflammatory cytokines and decreased anti-inflammatory factors, especially the hepatoprotective factor IL-10. The m6A modification writer WTAP could reduce the mRNA stability of AP-2α in a reader YTHDC1-dependent manner, whereas knockdown of WTAP or YTHDC1 enhances AP-2α expression and decreases lipid accumulation in HCC cells. Clinically, AP-2α expression negatively correlates with the expression of FASN, WTAP, YTHDC1 and the development of liver disease. Taken together, hepatocyte- or macrophage-specific deletion of Tfap2a promotes hepatic steatosis, fibrosis, and the development of HCC. These results suggest that AP-2α has been identified as a novel therapeutic target in fibrosis and inflammation-related HCC, exerting anti-lipogenesis, anti-inflammatory, and anti-tumor multi-roles.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/31 / 13/51 / 13/89 / 13/95 / 14/63 / 38/47 / 38/77 / 42/109 / 631/67/1504/1610 / 64/60 / 692/699/67/2329 / 82/80 / Animals / Antibodies / AP-2 protein / Biochemistry / Biomedical and Life Sciences / Carbon tetrachloride / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - metabolism / Carcinoma, Hepatocellular - pathology / Cell Biology / Cell Culture / Disease Progression / Fatty Acid Synthase, Type I / Fatty Acid Synthases - metabolism / Fatty liver / Fibrosis / Gene Deletion / Hepatocellular carcinoma / Hepatocytes / Hepatocytes - metabolism / Hepatocytes - pathology / Humans / Immunology / Inflammation / Interleukin-10 - metabolism / Leukocyte migration / Life Sciences / Lipids / Lipogenesis / Liver cancer / Liver diseases / Liver Neoplasms - genetics / Liver Neoplasms - metabolism / Liver Neoplasms - pathology / Macrophages / Macrophages - metabolism / Macrophages - pathology / Male / Mice / Mice, Inbred C57BL / Mice, Knockout / mRNA stability / N6-methyladenosine / Nitric-oxide synthase / Pathogenesis / Signal Transduction / Steatosis / Sterol Regulatory Element Binding Protein 1 - genetics / Sterol Regulatory Element Binding Protein 1 - metabolism / Therapeutic targets / Transcription Factor AP-2 - deficiency / Transcription Factor AP-2 - genetics / Transcription Factor AP-2 - metabolism / Transcription factors / Tumors