Glioblastoma multiforme (GBM) is the most common malignant tumour in the adult brain and hard to treat. Nuclear factor κB (NF‐κB) signalling has a crucial role in the tumorigenesis of GBM. EGFR signalling is an important driver of NF‐κB activation in GBM; however, the correlation between EGFR and the NF‐κB 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 IκBα and prevents the nuclear accumulation of the NF‐κB 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.

中文翻译：

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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-κB 激活中起关键作用。

多形性胶质母细胞瘤 (GBM) 是成人大脑中最常见的恶性肿瘤，难以治疗。核因子 κB (NF-κB) 信号传导在 GBM 的肿瘤发生中起着至关重要的作用。EGFR 信号传导是 GBM 中 NF-κB 激活的重要驱动因素；然而，EGFR 与 NF-κB 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 (MALT1) 在胶质瘤进展中的作用，并评估了 MI-2（一种 MALT1 抑制剂）在临床前 GBM 模型中的抗肿瘤活性和有效性。我们鉴定了一种参与 EGFR 诱导的 GBM 中 NF-kB 激活的副半胱天冬酶 MALT1。MALT1缺乏或抑制显着影响体外和体内GBM细胞的增殖、存活、迁移和侵袭。而且，MALT1 抑制通过调节多种细胞周期相关蛋白导致 G1 细胞周期停滞。从机制上讲，MALTI 抑制阻止了 IκBα 的降解，并阻止了 GBM 细胞中 NF-κB p65 亚基的核积累。本研究发现 MALT1 是一种关键的信号转导级联反应，可介导 EGFR 诱导的 GBM 中 NF-kB 活化，并可能用作 GBM 的新治疗靶点。