The University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine Pittsburgh, PA 15213, USA ; Departments of Surgery, University of Pittsburgh School of Medicine Pittsburgh, PA 15213, USA.
Am J Cancer Res. 2013;3(1):1-20. Epub 2013 Jan 18.
High mobility group box 1 (HMGB1), an evolutionarily highly conserved and abundant nuclear protein also has roles within the cytoplasm and as an extracellular damage-associated molecular pattern (DAMP) molecule. Extracellular HMGB1 is the prototypic endogenous 'danger signal' that triggers inflammation and immunity. Recent findings suggest that posttranslational modifications dictate the cellular localization and secretion of HMGB1. HMGB1 is actively secreted from immune cells and stressed cancer cells, or passively released from necrotic cells. During cancer development or administration of therapeutic agents including chemotherapy, radiation, epigenetic drugs, oncolytic viruses, or immunotherapy, the released HMGB1 may either promote or limit cancer growth, depending on the state of progression and vascularization of the tumor. Extracellular HMGB1 enhances autophagy and promotes persistence of surviving cancer cells following initial activation. When oxidized, it chronically suppresses the immune system to promote cancer growth and progression, thereby enhancing resistance to cancer therapeutics. In its reduced form, it can facilitate and elicit innate and adaptive anti-tumor immunity, recruiting and activating immune cells, in conjunction with cytotoxic agents, particularly in early transplantable tumor models. We hypothesize that HMGB1 also functions as an epigenetic modifier, mainly through regulation of NF-kB-dependent signaling pathways, to modulate the behavior of surviving cancer cells as well as the immune cells found within the tumor microenvironment. This has significant implications for developing novel cancer therapeutics.
高迁移率族蛋白 B1（HMGB1）是一种进化上高度保守且丰富的核蛋白，在细胞质中也具有作用，并且是细胞外损伤相关分子模式（DAMP）分子。细胞外 HMGB1 是触发炎症和免疫的典型内源性“危险信号”。最近的研究结果表明，翻译后修饰决定了 HMGB1 的细胞定位和分泌。HMGB1 可从免疫细胞和应激癌细胞中主动分泌，或从坏死细胞中被动释放。在癌症发展过程中或接受治疗剂治疗时，包括化疗、放疗、表观遗传药物、溶瘤病毒或免疫疗法，释放的 HMGB1 可能促进或限制癌症生长，具体取决于肿瘤的进展和血管化状态。细胞外 HMGB1 增强自噬，并促进存活癌细胞在初始激活后持续存在。当被氧化时，它会慢性抑制免疫系统，促进癌症生长和进展，从而增强对癌症治疗的耐药性。在其还原形式下，它可以促进和引发先天和适应性抗肿瘤免疫，招募和激活免疫细胞，与细胞毒性剂一起，特别是在早期可移植肿瘤模型中。我们假设 HMGB1 还作为一种表观遗传修饰物发挥作用，主要通过调节 NF-κB 依赖性信号通路，调节存活癌细胞以及肿瘤微环境中发现的免疫细胞的行为。这对开发新型癌症治疗方法具有重要意义。
