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. 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. 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. 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.

中文翻译：

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肝脏衰老相关的分泌表型通过 Bcl3 依赖性巨噬细胞活化促进肝癌发生

肝癌是世界上最常见的恶性肿瘤之一，预后较差。肝细胞癌（HCC）是最常见的原发性肝癌，占病例的 80-90%。HCC的发生和进展与慢性肝脏炎症密切相关。此外，HCC 常伴有细胞衰老。衰老肝细胞可以分泌多种炎症因子，统称为衰老相关分泌表型（SASP）。SASP已被证实通过影响炎症微环境促进肝癌的发生。然而，肝 SASP 在肝癌发生中的作用和潜在机制尚不清楚。因此，仍然需要更好地了解肝脏SASP对HCC发生的影响的发病机制。该研究旨在探讨 SASP 因子的作用及其在体内肿瘤发生和 HCC 进展中的潜在机制。我们使用二乙基亚硝胺 (DEN) 与四氯化碳 (CCl4) (DEN-CCl4) 结合在野生型 (WT) 小鼠和 Bcl3 敲除 (Bcl3-/-) 小鼠中建立肝癌模型。进行β-半乳糖苷酶（β-gal）染色以评估细胞衰老的程度。免疫组织化学（IHC）用于检测细胞衰老的程度和巨噬细胞的活化。PCR芯片和临床组织芯片分析用于估计SASP因子和NF-κB相关基因的RNA水平，并通过Western印迹分析检测它们的蛋白质水平。DEN-CCl4 诱导小鼠肝细胞衰老。此外，衰老的肝细胞可能会释放多种炎症因子，进一步激活巨噬细胞，从而改变微环境状态，促进 HCC 的发生。从机制上讲，NF-κB 通路很重要，因为它调节 SASP。因此，我们使用PCR芯片检测衰老肝组织中NF-κB相关基因的表达。我们的研究结果表明，Bcl3 在衰老肝细胞中的表达增加，敲除 Bcl3 可显着抑制肝细胞 SASP 因子的分泌和巨噬细胞的激活，从而抑制肝癌的发生。最后，在患者 HCC 组织附近的临床组织中，Bcl3 和 IL-8 的表达与 HCC 患者的不良预后相关。