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▎Editor of WuXi AppTec's content team On May 25th, Beijing time, the top international immunology journal Immunity published online the latest results of the collaboration between Gulou Hospital of Nanjing University School of Medicine and Nanjing University Institute of Modern Biology.
The research team led by Professor Sun Beicheng and Professor Lin Anning revealed a new mechanism by which liver inflammation promotes the occurrence and development of liver cancer, providing a new target for individualized treatment of liver cancer patients.
Liver cancer is the third leading cause of cancer-related deaths worldwide.
China is also a big country for liver cancer.
For the most common type of primary liver cancer, hepatocellular carcinoma (HCC), nearly half of the new cases worldwide occurred in China.
Hepatitis B virus infection, drinking, oncogene DNA damage, obesity and other factors can induce the inflammatory tumor microenvironment and promote the occurrence and development of liver cancer.
In this work, the research team proved that the abnormal activity of hepatocyte transcription factor NF-κB, whether it is missing or increased, can induce the inflammatory tumor microenvironment through different molecular mechanisms, thereby promoting the occurrence and development of liver cancer.
Image source: 123RF used two different mouse liver cancer models, and the researchers used single-cell sequencing to deeply analyze the interaction between liver cancer cells and macrophages in the liver cancer microenvironment.
The results showed that the transcription factor Miz1 in mouse liver cells is missing, which produces a specific “inflammatory” hepatocyte subpopulation that highly expresses NF-κB downstream inflammatory factors, activates tumor-infiltrating macrophages to transform into a pro-inflammatory phenotype, and enhances the liver Inflammation reaction promotes the occurrence and development of liver cancer.
Further mechanism studies found that the Miz1 protein located in the cytoplasm of liver cells is regulated by proteolysis induced by tumor necrosis factor TNF, and its expression is down-regulated in the process of liver cancer, thereby releasing the oncoprotein MTDH that binds to Miz1 and enhancing the protein kinase.
The phosphorylation of MTDH by IKK promotes the activation of NF-κB and the expression of downstream inflammatory factors in liver cells.It is worth noting that this mechanism of Miz1 does not depend on the function of its transcription factors.
In a considerable part of clinical liver cancer patients, Miz1 is lowly expressed in liver cancer tissues, accompanied by an increase in phosphorylation of MTDH and an increase in hepatocytes secreting inflammatory factors.
At the same time, the expression of Miz1 protein has also been confirmed to be closely related to the survival rate and recurrence rate of liver cancer patients, and is an independent prognostic related factor.
▲Schematic diagram of the research mechanism (picture source: reference [1]) In general, this study is based on multi-omics analysis, using a variety of in vivo and in vitro experiments, revealing that the lack of Miz1 protein in liver cells during the development of liver cancer is passed through MTDH The specific mechanism of activating NF-κB and enhancing inflammation puts forward an important hypothesis that hepatocytes as the main body of liver tumors drive cancer-promoting inflammation.
Professor Sun Beicheng, the corresponding author of the paper, commented: "Inflammation and tumors have always been the focus of our research.
Our study revealed that the lack of Miz1 in liver cells promotes the occurrence of liver cancer by activating the pro-inflammatory macrophage pathway, which means that the lack of Miz1 For patients with liver cancer, the therapeutic effect of targeting pro-inflammatory macrophages will be better.
Our team is developing mimic peptides of Miz1 and antibodies against MTDH phosphorylation for precise targeted therapy of liver cancer.
"This work was developed by Nanjing University School of Medicine.
Researchers from the Affiliated Drum Tower Hospital, the Institute of Modern Biology, Nanjing University, the University of Chicago, and the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.
Professor Sun Beicheng of the Drum Tower Hospital Affiliated to Nanjing University School of Medicine and Dr.
Lin Anning, a dual-appointed professor at the Nanjing University Institute of Modern Biology and Drum Tower Hospital, are the corresponding authors; Zhang Wenjie, deputy chief physician, PhD students Zhang Yuan Guangyan and Wang Fei, Nanjing University School of Medicine Drum Tower Hospital As the first author.
The Hepatobiliary and Pancreatic Center of Gulou Hospital is mainly engaged in the research of liver cancer immune microenvironment, liver surgery and liver transplantation.
The subject leader is Professor Sun Beicheng.
Talents at home and abroad are welcome to join. Reference: [1] Wenjie Zhang et al.
, (2021) The zinc finger protein Miz1 suppresses liver tumorigenesis by restricting hepatocyte-driven macrophage activation and inflammation.
Immunity.
Doi: https://doi.
org/10.
1016/j.
immuni .
2021.
04.
027
The research team led by Professor Sun Beicheng and Professor Lin Anning revealed a new mechanism by which liver inflammation promotes the occurrence and development of liver cancer, providing a new target for individualized treatment of liver cancer patients.
Liver cancer is the third leading cause of cancer-related deaths worldwide.
China is also a big country for liver cancer.
For the most common type of primary liver cancer, hepatocellular carcinoma (HCC), nearly half of the new cases worldwide occurred in China.
Hepatitis B virus infection, drinking, oncogene DNA damage, obesity and other factors can induce the inflammatory tumor microenvironment and promote the occurrence and development of liver cancer.
In this work, the research team proved that the abnormal activity of hepatocyte transcription factor NF-κB, whether it is missing or increased, can induce the inflammatory tumor microenvironment through different molecular mechanisms, thereby promoting the occurrence and development of liver cancer.
Image source: 123RF used two different mouse liver cancer models, and the researchers used single-cell sequencing to deeply analyze the interaction between liver cancer cells and macrophages in the liver cancer microenvironment.
The results showed that the transcription factor Miz1 in mouse liver cells is missing, which produces a specific “inflammatory” hepatocyte subpopulation that highly expresses NF-κB downstream inflammatory factors, activates tumor-infiltrating macrophages to transform into a pro-inflammatory phenotype, and enhances the liver Inflammation reaction promotes the occurrence and development of liver cancer.
Further mechanism studies found that the Miz1 protein located in the cytoplasm of liver cells is regulated by proteolysis induced by tumor necrosis factor TNF, and its expression is down-regulated in the process of liver cancer, thereby releasing the oncoprotein MTDH that binds to Miz1 and enhancing the protein kinase.
The phosphorylation of MTDH by IKK promotes the activation of NF-κB and the expression of downstream inflammatory factors in liver cells.It is worth noting that this mechanism of Miz1 does not depend on the function of its transcription factors.
In a considerable part of clinical liver cancer patients, Miz1 is lowly expressed in liver cancer tissues, accompanied by an increase in phosphorylation of MTDH and an increase in hepatocytes secreting inflammatory factors.
At the same time, the expression of Miz1 protein has also been confirmed to be closely related to the survival rate and recurrence rate of liver cancer patients, and is an independent prognostic related factor.
▲Schematic diagram of the research mechanism (picture source: reference [1]) In general, this study is based on multi-omics analysis, using a variety of in vivo and in vitro experiments, revealing that the lack of Miz1 protein in liver cells during the development of liver cancer is passed through MTDH The specific mechanism of activating NF-κB and enhancing inflammation puts forward an important hypothesis that hepatocytes as the main body of liver tumors drive cancer-promoting inflammation.
Professor Sun Beicheng, the corresponding author of the paper, commented: "Inflammation and tumors have always been the focus of our research.
Our study revealed that the lack of Miz1 in liver cells promotes the occurrence of liver cancer by activating the pro-inflammatory macrophage pathway, which means that the lack of Miz1 For patients with liver cancer, the therapeutic effect of targeting pro-inflammatory macrophages will be better.
Our team is developing mimic peptides of Miz1 and antibodies against MTDH phosphorylation for precise targeted therapy of liver cancer.
"This work was developed by Nanjing University School of Medicine.
Researchers from the Affiliated Drum Tower Hospital, the Institute of Modern Biology, Nanjing University, the University of Chicago, and the Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.
Professor Sun Beicheng of the Drum Tower Hospital Affiliated to Nanjing University School of Medicine and Dr.
Lin Anning, a dual-appointed professor at the Nanjing University Institute of Modern Biology and Drum Tower Hospital, are the corresponding authors; Zhang Wenjie, deputy chief physician, PhD students Zhang Yuan Guangyan and Wang Fei, Nanjing University School of Medicine Drum Tower Hospital As the first author.
The Hepatobiliary and Pancreatic Center of Gulou Hospital is mainly engaged in the research of liver cancer immune microenvironment, liver surgery and liver transplantation.
The subject leader is Professor Sun Beicheng.
Talents at home and abroad are welcome to join. Reference: [1] Wenjie Zhang et al.
, (2021) The zinc finger protein Miz1 suppresses liver tumorigenesis by restricting hepatocyte-driven macrophage activation and inflammation.
Immunity.
Doi: https://doi.
org/10.
1016/j.
immuni .
2021.
04.
027
