Project 2: Cytoplasmic chromatin fragments (CCF) as a driver of liver cancer and target for intervention during aging

项目摘要--项目2 肝癌(主要是肝细胞癌)的发病率正在增加，疾病转归 很穷。因此，迫切需要新的治疗方法和预防战略。年龄是一个主要的风险 用于肝癌和非酒精性脂肪性肝病(NAFLD)。非酒精性脂肪肝是一种慢性肝病，包括 肝细胞癌的严重程度和风险增加的疾病的进行性范围，从良性脂肪肝(脂肪变性)到 炎症性非酒精性脂肪性肝炎(NASH)、纤维化和肝硬变。衰老是伴随着许多人的 作为NAFLD和肝细胞癌候选驱动因素的分子、细胞和组织变化，包括 衰老“在不同的组织和生物体中随着年龄的增长而失控；例如，线粒体的变化， 代谢，表观基因组，衰老细胞的积累，炎症和免疫变化。 细胞衰老是由一系列细胞应激引起的，其特征是不可逆的 增殖停滞和一种强有力的促炎表型--衰老相关的分泌表型 (SASP)。最近，我们发现在衰老的细胞中，线粒体功能障碍的信号可以驱逐 染色质从细胞核进入细胞质(细胞质染色质碎片(CCF))通过核-到- 细胞质起泡过程。CCF被抗病毒胞质DNA传感装置感知到激活 NFkB和SASP。衰老细胞的SASP包括干扰素，这是一类与细胞有关的细胞因子 内在抗病毒机制、控制细胞增殖、炎症和获得性免疫与肿瘤 抑制和致癌过程。虽然SASP和急性干扰素信号传递有重要的好处，但慢性 SASP和干扰素信号可能是有害的。作为慢性炎症的来源，SASP促进组织衰老 和疾病，包括肝癌。慢性干扰素信号可以促进免疫抑制，部分是通过 上调免疫检查点抑制物，如PD-L1。 基于未发表的数据，我们假设CCF在衰老和/或衰老的肝脏中积累 肝细胞驱动干扰素信号的慢性激活、干扰素靶基因的表达和免疫检查点 抑制剂，如PD-L1。我们进一步假设，这反过来会产生免疫抑制的肝脏 允许老的肝细胞转化的微环境。通过对抗这个 免疫抑制信号通路，我们假设几种不同类型的干预可以防止 衰老过程中的肝癌。完成这些具体目标将促进预防肝细胞癌的新干预措施。

PROJECT SUMMARY – PROJECT 2 The incidences of liver cancer (primarily hepatocellular carcinoma (HCC)) are increasing and disease outcome is poor. Consequently, there is an urgent need for new therapies and preventive strategies. Age is a major risk for HCC and non-alcoholic fatty liver disease (NAFLD). NAFLD is a chronic liver disease that encompasses a progressive range of disorders of increasing severity and risk of HCC, from benign fatty liver (steatosis), to inflammatory non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Aging is accompanied by many molecular, cellular and tissue changes that are candidate drivers of NAFLD and HCC, including the “hallmarks of aging” that are dysregulated with age in diverse tissues and organisms; for example, changes to mitochondria, metabolism, the epigenome, accumulation of senescent cells, inflammation and immune changes. Cell senescence is caused by a range of cellular stresses and characterized by an irreversible proliferation arrest and a potent pro-inflammatory phenotype, the senescence-associated secretory phenotype (SASP). Recently, we showed that in senescent cells, mitochondria dysfunction signals to evict fragments of chromatin from the nucleus into the cytoplasm (cytoplasmic chromatin fragments (CCF)) via a nucleus-to- cytoplasmic blebbing process. CCF are sensed by the anti-viral cytoplasmic DNA sensing apparatus to activate NFkB and the SASP. The SASP of senescent cells includes interferons, a family of cytokines involved in cell intrinsic anti-viral mechanisms, control of cell proliferation, inflammation and adaptive immunity, and tumor suppressive and oncogenic processes. Although SASP and acute IFN signaling have important benefits, chronic SASP and IFN signaling can be detrimental. As a source of chronic inflammation, SASP promotes tissue aging and disease, including liver cancer. Chronic IFN signaling can promote immunosuppression, in part by upregulation of immune checkpoint inhibitors, such as PD-L1. Based on unpublished data, we hypothesize that accumulation of CCF in aged and/or senescent liver hepatocytes drives chronic activation of IFN signaling, expression of IFN target genes and immune checkpoint inhibitors, such as PD-L1. We further hypothesize that this, in turn, generates an immunosuppressed liver microenvironment that is permissive for transformation of old hepatocytes. By antagonizing this immunosuppressive signaling pathway, we hypothesize that several different types of intervention can prevent liver cancer during aging. Completion of these Specific Aims will promote novel interventions to prevent HCC.