PO.ET01.06 · 实验与分子治疗
HMGB1介导胶质母细胞瘤的化疗耐药和肿瘤进展：对靶向治疗的意义
HMGB1 mediates chemoresistance and tumor progression in glioblastoma: Implications for targeted therapy
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
胶质母细胞瘤（GBM）是最常见且最致命的原发性脑肿瘤，其特点是进展迅速、复发率高，尽管有当前的治疗干预，中位生存期仍不足15个月。由于肿瘤的浸润性特征和血脑屏障，手术切除、放疗和替莫唑胺（TMZ）化疗等标准治疗提供的获益有限。此外，GBM经常通过O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）介导的对化疗诱导DNA损伤的修复而对TMZ产生耐药，显著降低治疗效果。在治疗期间，GBM细胞和周围肿瘤微环境（TME）经历显著的生理应激，包括缺氧、炎症和DNA损伤。这些应激源诱导损伤相关分子模式（DAMP）的释放，其中高迁移率族蛋白B1（HMGB1）发挥关键作用。HMGB1是一种多功能核蛋白，根据其氧化还原状态和亚细胞定位，可调控肿瘤增殖、侵袭、血管生成和免疫调节。越来越多的证据表明，细胞外HMGB1通过与TME的免疫和基质成分的复杂相互作用促进肿瘤进展和治疗耐药。在本研究中，我们旨在使用整合的生物信息学方法和体外分析验证HMGB1的促肿瘤功能，以证实其在GBM病理和治疗耐药中的相关性。具体而言，我们探讨了HMGB1表达与TMZ耐药之间的相关性，检查其与MGMT表达以及下游信号通路（如MEK1/2-ERK1/2）激活的关联。通过阐明这些分子相互作用，我们旨在阐明HMGB1促进治疗耐药的机制。此外，我们进行了计算机模拟筛选，以鉴定具有同时抑制MGMT表达和TMZ耐药所涉及的其他关键成分潜力的HMGB1靶向抑制性化合物。总之，我们的发现旨在强化HMGB1作为预后生物标志物和治疗靶点的重要性，为GBM患者提供更有效和个性化治疗策略的新机会。
查看英文原文 English abstract
Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor, characterized by rapid progression, high recurrence rates, and a median survival of less than 15 months despite current therapeutic interventions. Standard treatments such as surgical resection, radiotherapy, and temozolomide (TMZ) chemotherapy offer limited benefit due to the infiltrative nature of the tumor and the blood-brain barrier. Moreover, GBM frequently develops resistance to TMZ through O6-methylguanine-DNA methyltransferase (MGMT)-mediated repair of chemotherapy-induced DNA damage, significantly reducing treatment effectiveness. During treatment, GBM cells and the surrounding tumor microenvironment (TME) undergo significant physiological stress, including hypoxia, inflammation, and DNA damage. These stressors induce the release of damage-associated molecular patterns (DAMPs), among which High Mobility Group Box 1 (HMGB1) plays a pivotal role. HMGB1 is a multifunctional nuclear protein that, depending on its redox state and subcellular localization, can regulate tumor proliferation, invasion, angiogenesis, and immune modulation. Accumulating evidence suggests that extracellular HMGB1 contributes to tumor progression and therapeutic resistance through complex interactions with immune and stromal components of the TME. In our present study, we aim to validate the protumorigenic functions of HMGB1 using integrated bioinformatic approaches and in vitro analyses to substantiate its relevance in GBM pathology and therapy resistance. Specifically, we explored the correlation between HMGB1 expression and TMZ resistance, examining its association with MGMT expression and the activation of downstream signaling pathways, such as MEK1/2-ERK1/2. By elucidating these molecular interactions, we aim to clarify the mechanisms through which HMGB1 promotes therapy resistance. Additionally, we performed in-silico screening to identify HMGB1-targeting inhibitory compounds with the potential to concurrently suppress MGMT expression and other crucial components involved in TMZ resistance. Collectively, our findings aim to reinforce the significance of HMGB1 as a prognostic biomarker and therapeutic target, offering new opportunities for more effective and personalized treatment strategies for GBM patients.
利益披露 Disclosure
S. Patra, None..
S. Banerjee, None..
M. Mandal, None.