細(xì)胞死亡是慢性肝病（CLD）疾病進(jìn)展和致癌作用的關(guān)鍵驅(qū)動因素，肝細(xì)胞死亡與肝硬化和肝細(xì)胞癌（HCC）發(fā)展風(fēng)險之間的臨床相關(guān)性凸顯了這一點。此外，肝細(xì)胞死亡足以觸發(fā)小鼠纖維化和 HCC。然而，細(xì)胞死亡驅(qū)動 CLD 進(jìn)展的途徑仍然難以捉摸。在這里，我們檢驗了高遷移率組盒 1 （HMGB1）的假設(shè)，這是一種在急性肝損傷中起關(guān)鍵作用的損傷相關(guān)分子模式（DAMP），可能與細(xì)胞死亡與 CLD 中的損傷反應(yīng)和肝癌發(fā)生有關(guān)。雖然肝臟特異性 HMGB1 缺陷不會顯著影響纖維化、再生和炎癥等慢性損傷反應(yīng)，但它抑制了導(dǎo)管/祖細(xì)胞擴(kuò)增和肝細(xì)胞化生。HMGB1 以非自主方式促進(jìn)獨立于主動分泌的導(dǎo)管擴(kuò)張，這與它作為 DAMP 的作用一致。肝臟特異性 HMGB1 缺陷減少了 3 種慢性損傷小鼠模型的 HCC 發(fā)展，但在缺乏慢性肝損傷的模型中沒有減少。與 CLD 一樣，HMGB1 消融降低了腫瘤中祖細(xì)胞和癌胎標(biāo)志物的表達(dá)，這是 HCC 侵襲性的關(guān)鍵決定因素。總之，HMGB1 將肝細(xì)胞死亡與 CLD 中的導(dǎo)管反應(yīng)、祖細(xì)胞特征和肝癌發(fā)生聯(lián)系起來。

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.

論文信息：

論文題目： HMGB1 links chronic liver injury to progenitor responses and hepatocarcinogenesis

期刊名稱：J Clin Invest.

時間期卷：2018;128(6):2436-2450.

在線時間：2018年3月20日

DOI：doi.org/10.1172/JCI91786.

產(chǎn)品信息：

貨號：CP-005-005

規(guī)格：5ml+5ml

品牌：Liposoma

產(chǎn)地：荷蘭

名稱：Clodronate Liposomes and Control Liposomes