NDLI: The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages

Content Provider	Springer Nature : BioMed Central
Author	Huang, Yihua Yang, Xue Meng, Yan Shao, Changchun Liao, Jianping Li, Fengwei Li, Rong Jing, Yingying Huang, Aimin
Abstract	Background Liver cancer is one of the most common malignancies in the world with a poor prognosis. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80–90% of cases. The initiation and progression of HCC are closely associated with chronic liver inflammation. In addition, HCC is often accompanied by cell senescence. Senescent hepatocytes can secrete various inflammatory factors, collectively called the senescence-associated secretory phenotype (SASP). The SASP has been confirmed to promote the occurrence of liver cancer by affecting the inflammatory microenvironment. However, its role and the underlying mechanism of hepatic SASP in hepatocarcinogenesis are not clearly understood. Therefore, a better understanding of the pathogenic mechanisms of the effect of the hepatic SASP on the occurrence of HCC is still needed. Methods The study aims to explore the role of SASP factors and the underlying mechanism in tumorigenesis and the progression of HCC in vivo. We used diethylnitrosamine (DEN) combined with carbon tetrachloride (CCl4) (DEN-CCl4) to establish liver cancer model in wild-type (WT) mice and Bcl3 knockout (Bcl3−/−) mice. β-galactosidase (β-gal) staining was performed to evaluate the degree of cellular senescence. Immunohistochemistry (IHC) were used to detect the degree of cellular senescence and the activation of macrophage. PCR chip and clinical tissue chip assays were used to estimate the RNA levels of SASP factors and NF-κB related genes, and their protein levels were examined by Western blot assays. Results DEN-CCl4 induced cellular senescence in mouse hepatocytes. In addition, senescent hepatocytes might release a variety of inflammatory factors that further activate macrophages, thereby changing the microenvironmental state and promoting the occurrence of HCC. Mechanistically, the NF-κB pathway is important because it regulates the SASP. Therefore, we used a PCR chip to detect the expression of NF-κB-related genes in senescent liver tissue. Our results showed that the expression of Bcl3 was increased in senescent hepatocytes, and knocking out Bcl3 significantly inhibited the secretion of hepatocyte SASP factors and the activation of macrophages, thereby inhibiting hepatocarcinogenesis. Finally, in clinical tissues adjacent to HCC tissues in patients, the expression of Bcl3 and IL-8 correlated with poor prognosis in HCC patients. Conclusion The hepatic SASP can further induce the activation of macrophages during hepatocarcinogenesis, thereby promoting the occurrence of HCC, and that this process is closely related to the expression of Bcl3 in hepatocytes.
Related Links	https://cellandbioscience.biomedcentral.com/counter/pdf/10.1186/s13578-021-00683-5.pdf
Ending Page	14
Page Count	14
Starting Page	1
File Format	HTM / HTML
ISSN	20453701
DOI	10.1186/s13578-021-00683-5
Journal	Cell & Bioscience
Issue Number	1
Volume Number	11
Language	English
Publisher	BioMed Central
Publisher Date	2021-09-16
Access Restriction	Open
Subject Keyword	Cell Biology Microbiology Stem Cells Neurobiology Proteomics Liver cancer Hepatic senescence-associated secretory phenotype Bcl3 Macrophage
Content Type	Text
Resource Type	Article
Subject	Biochemistry, Genetics and Molecular Biology
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	7/2023

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