HMGB1 as Link Between Hepatocellular Injury and HCC

 描述（由申请人提供）：肝细胞癌（HCC）是全球癌症死亡的第三大原因。在美国，HCC发病率和HCC相关死亡率在过去三十年中显著增加，而大多数其他实体瘤的发病率和死亡率则有所下降。HCC几乎完全在慢性肝病（CLD）的背景下发展，并且是慢性肝细胞死亡的直接和临床上最具破坏性的后果。ALT >45 U/l的患者与ALT正常的患者相比，HCC风险增加7-10倍，这突出了细胞死亡与HCC之间的联系。在小鼠中，慢性肝细胞损伤足以在没有额外遗传命中的情况下触发HCC的发展。因此，HCC是“癌症是一个无法愈合的伤口”这一假设的典型例子。然而，将肝细胞损伤与癌发生联系起来的分子机制仍然难以捉摸。了解参与这一过程的介质可能允许药物阻断肝细胞损伤的促癌作用，因此可能为慢性肝损伤患者开发癌症预防治疗提供基础。在这里，我们试图测试的假设，损伤相关的分子模式（DAMPs）从受损的肝细胞提供了细胞死亡和肝癌发生之间的分子联系。基于大量的初步数据表明HMGB 1在损伤肝脏的肝细胞死亡反应中的核心作用-包括中性粒细胞的募集和祖细胞的扩增-我们试图证明DAMP高迁移率族蛋白1（HMGB 1）通过驱动适应不良和肿瘤促进伤口愈合将肝细胞死亡与致癌联系起来的假设。在小鼠中使用HMBG 1的条件性消融，我们将确定HMGB 1在损伤驱动和纯遗传毒性HCC模型中的作用，并确定药理学HMGB 1抑制是否可以预防HCC的发展（目的1）。基于我们的发现，（i）HMGB 1在通过嗜中性粒细胞表达的TNF α向损伤的肝细胞募集中性粒细胞中具有关键作用，以及（ii）募集的中性粒细胞在功能上有助于肝癌发生并直接触发肝细胞中的DNA损伤，我们将确定HMGB 1的作用中性粒细胞的募集及其通过包括中性粒细胞在内的特异性效应通路在肝癌发生中的作用弹性蛋白酶和中性粒细胞胞外陷阱（Aim 2）。最后，我们将确定HMGB 1-β轴是否向上皮隔室提供信号，以触发肿瘤内祖细胞的扩增和/或祖细胞表型的获得，这两者都已知会增加癌症风险和恶化预后（Aim 3）。总之，拟议的实验不仅将为肝细胞死亡和HCC发展之间的联系提供机制解释，而且还可能为HCC的预防和治疗提供新的靶点。

 DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. In the US, HCC rates and HCC-related deaths have increased significantly in the past three decades, whereas incidence and mortality for most other solid tumors have declined. HCC develops almost exclusively in the setting of chronic liver disease (CLD), and is a direct and the clinically most devastating consequence of chronic hepatocellular death. The link between cell death and HCC is highlighted by a 7-10 fold increase in HCC risk in patients with ALT >45 U/l in comparison to those with normal ALT. In mice, chronic hepatocellular injury is sufficient to trigger HCC development in the absence of additional genetic hits. Hence, HCC is a prototypical example for the hypothesis that "cancer is a wound that does not heal". However, molecular mechanisms that link hepatocellular injury to carcinogenesis remain elusive. Knowledge about mediators involved in this process may allow pharmacologic blockade of the cancer-promoting effects of hepatocellular injury, and hence may provide a basis for developing cancer prevention therapies for patients with chronic liver injury. Here we seek to test the hypothesis that damage-associated molecular patterns (DAMPs) from injured hepatocytes provide a molecular link between cell death and hepatocarcinogenesis. Based on abundant preliminary data demonstrating a central role for HMGB1 in hepatic cell death responses in the injured liver - including the recruitment of neutrophils and the expansion of progenitors - we seek to prove the hypothesis that the DAMP high-mobility group box 1 (HMGB1), links hepatocellular death to carcinogenesis by driving maladaptive and tumor-promoting wound healing. Using conditional ablation of HMBG1 in mice, we will determine the role of HMGB1 in injury-driven and purely genotoxic HCC models, and determine whether pharmacologic HMGB1 inhibition prevents HCC development (Aim 1). Based on our findings that (i) HMGB1 has a key role in recruiting neutrophils towards injured hepatocytes via neutrophil-expressed RAGE and (ii) that recruited neutrophils functionally contribute to hepatocarcinogenesis and directly trigger DNA damage in hepatocytes, we will determine the role of the HMGB1-RAGE axis in the recruitment of neutrophils and their functional contribution to hepatocarcinogenesis via specific effector pathways including neutrophil elastase and neutrophil extracellular traps (Aim 2). Finally, we will determine whether the HMGB1-RAGE axis provides a signal to the epithelial compartment to trigger the expansion of progenitors and/or the acquisition of a progenitor phenotype within tumors, which are both known to increase cancer risk and worsen prognosis (Aim 3). Together, the proposed experiments will not only provide a mechanistic explanation for the link between hepatocellular death and HCC development, but may also provide novel targets for HCC prevention and treatment.