Miz1 Restricts Hepatocyte-driven Inflammation Independently Of Its Transcriptional Activity In Liver Tumorigenesis

Chronic inflammation has a central role in hepatocellular carcinoma(HCC).However,the contribution of tumor hepatocytes to tumor-associated inflammation is not fully understood.Here we report that Mizl restricts hepatocyte-driven inflammation,which otherwise exacerbates HCC,independently of its transcriptional activity.Mizl is downregulated in HCC mouse models and a significant fraction of patients.Hepatocyte-specific Mizl deletion generates a unique sub-group of hepatocytes that produces pro-inflammatory cytokines and chemokines,thereby skewing the polarization of tumor-infiltrating macrophage toward pro-inflammatory phenotype to promote carcinogen-or NASH-induced HCC.By sequestrating Metadherin(MTDH)and inhibiting its IKK-mediated phosphorylation,Mizl suppresses MTDH-mediated RelA nuclear translocation and transcription activity.Pro-inflammatory cytokineproducing hepatocytes are increased,whereas Mizl expression is decreased along with augmented phosphorylation of hepatocyte RelA and MTDH in a significant fraction of HCC patients with disease recurrence and poor prognosis.Our findings identify Mizl as a tumor suppressor that prevents hepatocytes from driving inflammation in HCC.