HMGB1 as Link Between Hepatocellular Injury and HCC

 描述(申请人提供)：肝细胞癌是全球癌症死亡的第三大原因。在美国，在过去30年中，肝癌发病率和与肝癌相关的死亡显著增加，而大多数其他实体肿瘤的发病率和死亡率下降。肝癌几乎完全发生在慢性肝病(CLD)的背景下，是慢性肝细胞死亡的直接和临床上最具破坏性的后果。与ALT正常的患者相比，ALT&GT；45U/L患者的肝癌风险增加了7-10倍，突显了细胞死亡与肝癌之间的联系。在小鼠中，慢性肝细胞损伤足以在没有额外基因打击的情况下引发肝细胞癌的发生。因此，肝癌是“癌症是无法愈合的伤口”这一假说的典型例子。然而，将肝细胞损伤与癌变联系起来的分子机制仍然难以捉摸。对参与这一过程的介质的了解可能会使药物阻断肝细胞损伤的促癌作用，从而可能为开发慢性肝损伤患者的癌症预防治疗提供基础。在这里，我们试图检验一种假设，即受损肝细胞的损伤相关分子模式(DAMP)在细胞死亡和肝癌发生之间提供了分子联系。基于大量的初步数据表明HMGB1在受损肝脏的肝细胞死亡反应中发挥中心作用-包括中性粒细胞的募集和祖细胞的扩张-我们试图证明这一假设，即潮湿的高迁移率族蛋白1(HMGB1)通过推动适应不良和促进肿瘤的伤口愈合而将肝细胞死亡与癌症发生联系起来。通过在小鼠中有条件地切除HMBG1，我们将确定HMGB1在损伤驱动和纯基因毒性肝癌模型中的作用，并确定药物抑制HMGB1是否可以阻止肝癌的发展(目标1)。根据我们的研究结果，(I)HMGB1通过中性粒细胞表达的RAGE在中性粒细胞向受损肝细胞募集方面发挥关键作用，(Ii)在功能上募集中性粒细胞导致肝癌发生并直接引发肝细胞DNA损伤，我们将确定HMGB1-RAGE轴在中性粒细胞募集中的作用及其通过包括中性粒细胞弹性蛋白酶和中性粒细胞外陷阱在内的特定效应途径在肝癌发生中的功能贡献(目标2)。最后，我们将确定HMGB1-RAGE轴是否向上皮室提供信号，以触发肿瘤内祖细胞的扩张和/或获得祖细胞表型，这两者都已知会增加癌症风险和恶化预后(目标3)。总之，拟议的实验不仅将为肝细胞死亡和肝细胞癌发展之间的联系提供机制解释，而且还可能为肝细胞癌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.