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

• Published in: Immunity (Cambridge, Mass.) Vol. 54; no. 6; pp. 1168 - 1185.e8
• Main Authors: Zhang, Wenjie, Zhangyuan, Guangyan, Wang, Fei, Jin, Kangpeng, Shen, Haiyuan, Zhang, Liansheng, Yuan, Xiang, Wang, Jincheng, Zhang, Haitian, Yu, Weiwei, Huang, Ruyi, Xu, Xiaoliang, Yin, Yin, Zhong, Guisheng, Lin, Anning, Sun, Beicheng
• Format: Journal Article
• Language: English
• Published: Cambridge Elsevier Inc 08-06-2021; Elsevier Limited
• Subjects: Animal models; Apoptosis; Cell activation; Cell cycle; Chemokines; Cytokines; Genes; HCC; Hepatitis; Hepatocellular carcinoma; hepatocyte NF-κB; Hepatocytes; Infections; Inflammation; Kinases; Liver cancer; Macrophages; Medical prognosis; metadherin; Miz1; MTDH; NF-κB protein; Phenotypes; Rodents; scRNA-seq; Tumor necrosis factor-TNF; Tumor suppressor genes; Tumorigenesis; Tumors; Viral infections; Zinc; Zinc finger proteins; hepatocyte NF-κB; scRNA-seq; inflammation; Miz1; HCC; metadherin; hepatocellular carcinoma; MTDH
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.04.027

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.
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•Miz1 suppresses liver cancer independently of its transcriptional activity•Miz1 restricts the ability of hepatocytes to drive macrophage-dependent inflammation•Miz1 prevents oncoprotein MTDH from promoting hepatocyte NF-κB activity•Miz1 expression inversely correlates with recurrence and poor prognosis in HCC patients
Chronic inflammation plays a crucial role in hepatocellular carcinoma (HCC), but the contribution of tumor hepatocytes to tumor-associated inflammation remains unclear. Zhang et al. find that loss of the transcription factor Miz1 in hepatocytes promotes NF-κB activation, producing a distinct sub-cluster of tumor hepatocytes that skew tumor-infiltrating macrophages toward a pro-inflammatory phenotype and drive inflammation in HCC.