Liver cancer is the third leading cause of cancer-related deaths worldwide. China is also a major country in liver cancer. For hepatocellular carcinoma (HCC), the most common primary type of liver cancer, nearly half of the new cases in the world occur in China.
In summary, based on multi-omics analysis and using a variety of in vivo and in vitro experiments, this study reveals the specific mechanism of MIZ1 protein deficiency in liver cells activating NF-κB and enhancing inflammation through MTDH during the development of liver cancer, and proposes an important hypothesis that hepatocytes, as the main body of liver tumors, drive cancer inflammation.
Corresponding author of the paper, Professor Sun Beicheng commented: "Inflammation and cancer has been the focus of our research, we study reveals the lack of liver cell Miz1 by activating proinflammatory macrophages way promote liver cancer, which means that the lack of Miz1 in patients with liver cancer, targeted proinflammatory macrophages treatment effect will be better, our team is developing Miz1 simulation peptides and antibodies against MTDH phosphorylation, To target liver cancer precisely."
Various factors, such as hepatitis B virus infection, alcohol consumption, DNA damage of oncogenes and obesity, can induce inflammatory tumor microenvironment and promote the occurrence and development of liver cancer. In this work, the team demonstrated that abnormal activity of the hepatocellular transcription factor NF-κB, whether deficient or elevated, induces an inflammatory tumor microenvironment through various molecular mechanisms and promotes the development and progression of HCC.
Using two different mouse liver cancer models, we analyzed the interaction between HCC cells and macrophages in depth in the HCC microenvironment by single-cell sequencing. The results showed that the deletion of transcription factor Miz1 in mouse hepatocytes resulted in the generation of specific "inflammatory" hepatocyte subsets with high expression of downstream inflammatory factors of NF-κB, which activated the transformation of tumor-infiltrating macrophages into pro-inflammatory phenotype, enhanced liver inflammatory response, and promoted the occurrence and development of liver cancer.
Further mechanism studies showed that MIZ1 protein located in hepatocyte cytoplasm was regulated by TNF-induced proteolysis, and its expression was down-regulated during the process of liver cancer, thus releasing MIZ1-bound oncoprotein MTDH, which enhanced the phosphorylation of MTDH by protein kinase IKK. It can promote the activation of NF-κB and the expression of downstream inflammatory factors in liver cells.
Notably, this mechanism of MIZ1 does not depend on the function of its transcription factor. In a considerable number of clinical HCC patients, the low expression of MIZ1 in HCC tissues is accompanied by the enhancement of MTDH phosphorylation and the increase of hepatocytes secreting inflammatory factors. At the same time, the expression of MIZ1 protein has also been proved to be closely related to the survival rate and recurrence rate of liver cancer patients, and is an independent prognostic associated factor.