MALT1 is a potential therapeutic target in glioblastoma and plays a crucial role in EGFR-induced NF-κB activation
MALT1 is a potential therapeutic target in glioblastoma and plays a crucial role in EGFR-induced NF-κB activation
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MALT1 是胶质母细胞瘤的潜在治疗靶点，在 EGFR 诱导的 NF-κ B 激活中发挥着至关重要的作用
DOI：
10.1111/jcmm.15383
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发表时间：
2020-05-25
影响因子：
5.3
通讯作者：
Yu, Rutong
中科院分区：
文献类型：
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作者：
Liu, Xuejiao;Yue, Chenglong;Yu, Rutong
多形性胶质母细胞瘤（GBM）是成人脑内最常见的恶性肿瘤，治疗困难，核因子-κ B（NF-κ B）信号在GBM的发生发展中起重要作用。EGFR信号传导是GBM中NF-κ B活化的重要驱动因素;然而，EGFR与NF-κ B通路之间的相关性仍不清楚。在这项研究中，我们研究了粘膜相关淋巴瘤抗原1（MALT 1）在胶质瘤进展中的作用，并评估了MI-2（一种MALT 1抑制剂）在临床前GBM模型中的抗肿瘤活性和有效性。我们鉴定了一种paracaspase MALT 1，它参与了GBM中EGFR诱导的NF-κ B活化。MALT 1的缺失或抑制显著影响GBM细胞在体外和体内的增殖、存活、迁移和侵袭。此外，MALT 1抑制通过调节多种细胞周期相关蛋白引起G1期细胞周期阻滞。在机制上，MALTI抑制阻断I κ B α的降解并防止NF-κ B p65亚基在GBM细胞中的核积累。本研究发现，MALT 1是一个关键的信号转导级联，可以介导EGFR诱导的GBM中NF-κ B活化，并可能用作GBM的新的治疗靶点。
Glioblastoma multiforme (GBM) is the most common malignant tumour in the adult brain and hard to treat. Nuclear factor kappa B (NF-kappa B) signalling has a crucial role in the tumorigenesis of GBM. EGFR signalling is an important driver of NF-kappa B activation in GBM; however, the correlation between EGFR and the NF-kappa B pathway remains unclear. In this study, we investigated the role of mucosa-associated lymphoma antigen 1 (MALT1) in glioma progression and evaluated the anti-tumour activity and effectiveness of MI-2, a MALT1 inhibitor in a pre-clinical GBM model. We identified a paracaspase MALT1 that is involved in EGFR-induced NF-kB activation in GBM. MALT1 deficiency or inhibition significantly affected the proliferation, survival, migration and invasion of GBM cells both in vitro and in vivo. Moreover, MALT1 inhibition caused G1 cell cycle arrest by regulating multiple cell cycle-associated proteins. Mechanistically, MALTI inhibition blocks the degradation of I kappa B alpha and prevents the nuclear accumulation of the NF-kappa B p65 subunit in GBM cells. This study found that MALT1, a key signal transduction cascade, can mediate EGFR-induced NF-kB activation in GBM and may be potentially used as a novel therapeutic target for GBM.