中文摘要:
细胞死亡是慢性肝病 (CLD) 疾病进展和致癌作用的关键驱动因素,肝细胞死亡与肝硬化和肝细胞癌 (HCC) 发展风险之间的临床相关性凸显了这一点。此外,肝细胞死亡足以触发小鼠纤维化和 HCC。然而,细胞死亡驱动 CLD 进展的途径仍然难以捉摸。在这里,我们检验了高迁移率组盒 1 (HMGB1) 的假设,这是一种在急性肝损伤中起关键作用的损伤相关分子模式 (DAMP),可能与细胞死亡与 CLD 中的损伤反应和肝癌发生有关。虽然肝脏特异性 HMGB1 缺陷不会显着影响纤维化、再生和炎症等慢性损伤反应,但它抑制了导管/祖细胞扩增和肝细胞化生。HMGB1 以非自主方式促进独立于主动分泌的导管扩张,这与它作为 DAMP 的作用一致。肝脏特异性 HMGB1 缺陷减少了 3 种慢性损伤小鼠模型的 HCC 发展,但在缺乏慢性肝损伤的模型中没有减少。与 CLD 一样,HMGB1 消融降低了肿瘤中祖细胞和癌胎标志物的表达,这是 HCC 侵袭性的关键决定因素。总之,HMGB1 将肝细胞死亡与 CLD 中的导管反应、祖细胞特征和肝癌发生联系起来。
英文摘要:
Cell death is a key driver of disease progression and carcinogenesis in chronic liver disease (CLD), highlighted by the well-established clinical correlation between hepatocellular death and risk for the development of cirrhosis and hepatocellular carcinoma (HCC). Moreover, hepatocellular death is sufficient to trigger fibrosis and HCC in mice. However, the pathways through which cell death drives CLD progression remain elusive. Here, we tested the hypothesis that high-mobility group box 1 (HMGB1), a damage-associated molecular pattern (DAMP) with key roles in acute liver injury, may link cell death to injury responses and hepatocarcinogenesis in CLD. While liver-specific HMGB1 deficiency did not significantly affect chronic injury responses such as fibrosis, regeneration, and inflammation, it inhibited ductular/progenitor cell expansion and hepatocyte metaplasia. HMGB1 promoted ductular expansion independently of active secretion in a nonautonomous fashion, consistent with its role as a DAMP. Liver-specific HMGB1 deficiency reduced HCC development in 3 mouse models of chronic injury but not in a model lacking chronic liver injury. As with CLD, HMGB1 ablation reduced the expression of progenitor and oncofetal markers, a key determinant of HCC aggressiveness, in tumors. In summary, HMGB1 links hepatocyte death to ductular reaction, progenitor signature, and hepatocarcinogenesis in CLD.
论文信息:
论文题目: HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis
期刊名称:J Clin Invest.
时间期卷:2018;128(6):2436-2450.
在线时间:2018年3月20日
DOI:doi.org/10.1172/JCI91786.
产品信息:
货号:CP-005-005
规格:5ml+5ml
品牌:Liposoma
产地:荷兰
名称:Clodronate Liposomes and Control Liposomes
办事处:Target Technology(靶点科技)
Clodronate Liposomes氯膦酸盐脂质体助力慢性肝损伤与癌症模型巨噬细胞研究,荷兰Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于JCI:
Liposoma巨噬细胞清除剂ClodronateLiposomes氯膦酸二钠脂质体的材料和方法: