EB病毒相关鼻咽癌中HMGB1的翻译后修饰：当前证据、新兴机制概念及未解决问题

文献信息

中文摘要

鼻咽癌（NPC）是一种地理分布独特的恶性肿瘤，与EB病毒（EBV）感染密切相关，其特征是在高度免疫抑制的肿瘤微环境（TME）中发生广泛的表观遗传重编程。高迁移率族蛋白B1（HMGB1）是一种多功能的染色质结合蛋白，也可作为细胞外损伤相关分子模式（DAMP），已成为基因组组织、转录控制、细胞应激反应和免疫信号传导的重要调节因子。据报道，NPC中HMGB1表达增加，并与不良临床病理特征和患者预后差相关。新出现的证据表明，HMGB1的多种生物学功能受翻译后修饰（PTM）影响，这些修饰影响其亚细胞定位、分子相互作用和细胞外信号传导功能。通过这些调控机制，HMGB1可能从核染色质相关蛋白转变为免疫和炎症反应的细胞外介质。包括乙酰化、磷酸化、糖基化、氧化、甲基化和乳酸化在内的PTM已被认为参与调节HMGB1的转运和功能，尽管其中许多修饰在NPC中的具体作用仍未完全阐明。在这篇综述中，我们总结了关于HMGB1 PTM的当前证据，并讨论了它们对EBV相关NPC的潜在意义，重点关注核调控、免疫串扰和治疗反应。我们明确区分了在NPC中直接证实的研究结果与来自其他恶性肿瘤和相关疾病模型的机制见解，并指出了所提出的机制在NPC中仍处于假设生成而非实验验证的领域。通过将当前证据与新兴机制概念相结合，我们强调了关键知识空白、未解决问题以及未来研究的优先事项。更好地理解PTM依赖的HMGB1调控可能有助于为EBV相关NPC开发新的生物标志物和治疗策略。

英文摘要

Nasopharyngeal carcinoma (NPC) is a geographically distinct malignancy closely associated with Epstein-Barr virus (EBV) infection and characterized by extensive epigenetic reprogramming within a highly immunosuppressive tumor microenvironment (TME). High-mobility group box 1 (HMGB1), a multifunctional chromatin-binding protein that can also act as an extracellular damage-associated molecular pattern (DAMP), has emerged as an important regulator of genome organization, transcriptional control, cellular stress responses, and immune signaling. Increased HMGB1 expression has been reported in NPC and is associated with adverse clinicopathological features and poor patient outcomes. Emerging evidence suggests that the diverse biological functions of HMGB1 are influenced by post-translational modifications (PTMs), which affect its subcellular localization, molecular interactions, and extracellular signaling functions. Through these regulatory mechanisms, HMGB1 may transition from a nuclear chromatin-associated protein to an extracellular mediator of immune and inflammatory responses. PTMs including acetylation, phosphorylation, glycosylation, oxidation, methylation, and lactylation have been implicated in regulating HMGB1 trafficking and function, although the specific roles of many of these modifications in NPC remain incompletely characterized. In this review, we summarize current evidence regarding HMGB1 PTMs and discuss their potential implications for EBV-associated NPC, with emphasis on nuclear regulation, immune crosstalk, and therapeutic response. We explicitly distinguish findings directly demonstrated in NPC from mechanistic insights derived from other malignancies and related disease models, and identify areas where proposed mechanisms remain hypothesis-generating rather than experimentally validated in NPC. By integrating current evidence with emerging mechanistic concepts, we highlight key knowledge gaps, unresolved questions, and priorities for future research. A better understanding of PTM-dependent HMGB1 regulation may facilitate the development of novel biomarker and therapeutic strategies for EBV-associated NPC.