The zinc finger protein Miz1 suppresses liver tumorigenesis by restricting hepatocyte-driven macrophage activation and inflammation

• DOI: 10.1016/j.immuni.2021.04.027
• Publication Date: 2021-05-25T15:34:55Z
• Authors: Wenjie Zhang; Guangyan Zhangyuan; Fei Wang; Kangpeng Jin; Haiyuan Shen; Liansheng Zhang; Xiang Yuan; Jincheng Wang; Haitian Zhang; Weiwei Yu; Ruyi Huang; Xiaoliang Xu; Yin Yin; Guisheng Zhong; Anning Lin; Beicheng Sun
• Keywords: Inflammation; Male; 0301 basic medicine; Carcinoma, Hepatocellular; Carcinogenesis; Liver Neoplasms; NF-kappa B; Down-Regulation; Macrophage Activation; Protein Inhibitors of Activated STAT; Cell Line; Mice, Inbred C57BL; Mice; 03 medical and health sciences; HEK293 Cells; Liver; Cell Line, Tumor; Hepatocytes; Animals; Humans; Female; Chemokines

Chronic inflammation plays a central role in hepatocellular carcinoma (HCC), but the contribution of hepatocytes to tumor-associated inflammation is not clear. Here, we report that the zinc finger transcription factor Miz1 restricted hepatocyte-driven inflammation to suppress HCC, independently of its transcriptional activity. Miz1 was downregulated in HCC mouse models and a substantial fraction of HCC patients. Hepatocyte-specific Miz1 deletion in mice generated a distinct sub-group of hepatocytes that produced pro-inflammatory cytokines and chemokines, which skewed the polarization of the tumor-infiltrating macrophages toward pro-inflammatory phenotypes to promote HCC. Mechanistically, Miz1 sequestrated the oncoprotein metadherin (MTDH), preventing MTDH from promoting transcription factor nuclear factor κB (NF-κB) activation. A distinct sub-group of pro-inflammatory cytokine-producing hepatocytes was also seen in a subset of HCC patients. In addition, Miz1 expression inversely correated with disease recurrence and poor prognosis in HCC patients. Our findings identify Miz1 as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC.