PDF(Pubmed)
Abstract：
MALT1 has been implicated as an upstream regulator of NF-κB signaling in immune cells and tumors. This study determined the regulatory mechanisms and biological functions of MALT1 in non-small cell lung cancer (NSCLC). In cell culture and orthotopic xenograft models, MALT1 suppression via gene expression interference or protein activity inhibition significantly impaired malignant phenotypes and enhanced radiation sensitivity of NSCLC cells. CSN5, the core subunit of COP9 signalosome, was firstly verified to stabilize MALT1 via disturbing the interaction with E3 ligase FBXO3. Loss of FBXO3 in NSCLC cells reduced MALT1 ubiquitination and promoted its accumulation, which was reversed by CSN5 interference. An association between CSN5/FBXO3/MALT1 regulatory axis and poor prognosis in NSCLC patients was identified. Our findings revealed the detail mechanism of continuous MALT1 activation in NF-κB signaling, highlighting its significance as predictor and potential therapeutic target in NSCLC.
摘要：
MALT1已被认为是免疫细胞和肿瘤中NF-κB信号传导的上游调节剂。本研究确定了MALT1在非小细胞肺癌（NSCLC）中的调控机制和生物学功能。在细胞培养和原位异种移植模型中，通过基因表达干扰或蛋白活性抑制的MALT1抑制显著损害NSCLC细胞的恶性表型和增强的放射敏感性。CSN5，COP9信号体的核心亚基，首先验证了通过干扰与E3连接酶FBXO3的相互作用来稳定MALT1。FBXO3在NSCLC细胞中的丢失减少了MALT1的泛素化并促进其积累，被CSN5干扰逆转。CSN5/FBXO3/MALT1调节轴与NSCLC患者的不良预后之间的关联被确定。我们的发现揭示了NF-κB信号传导中持续MALT1激活的详细机制，强调其作为NSCLC预测因子和潜在治疗靶点的意义。
