文章目录

LncRNA Malat1抑制热亡和T细胞介导的早期转移细胞的杀伤

原文发布日期：2024-01-09

英文摘要：

摘要翻译：

原文链接：

文章：

LncRNA Malat1抑制热亡和T细胞介导的早期转移细胞的杀伤

LncRNA Malat1 suppresses pyroptosis and T cell-mediated killing of incipient metastatic cells

原文发布日期：2024-01-09

英文摘要：

The contribution of antitumor immunity to metastatic dormancy is poorly understood. Here we show that the long noncoding RNA Malat1 is required for tumor initiation and metastatic reactivation in mouse models of breast cancer and other tumor types. Malat1 localizes to nuclear speckles to couple transcription, splicing and mRNA maturation. In metastatic cells, Malat1 induces WNT ligands, autocrine loops to promote self-renewal and the expression of Serpin protease inhibitors. Through inhibition of caspase-1 and cathepsin G, SERPINB6B prevents gasdermin D-mediated induction of pyroptosis. In this way, SERPINB6B suppresses immunogenic cell death and confers evasion of T cell-mediated tumor lysis of incipient metastatic cells. On-target inhibition of Malat1 using therapeutic antisense nucleotides suppresses metastasis in a SERPINB6B-dependent manner. These results suggest that Malat1-induced expression of SERPINB6B can titrate pyroptosis and immune recognition at metastatic sites. Thus, Malat1 is at the nexus of tumor initiation, reactivation and immune evasion and represents a tractable and clinically relevant drug target.

摘要翻译：

抗肿瘤免疫对转移性睡眠期的贡献尚不明确。在这里，我们发现，在小鼠乳腺癌和其他肿瘤类型模型中，长非编码RNA Malat1对于肿瘤初始化和转移性重编程是必要的。在转移性细胞中，Malat1诱导WNT信号配体，并通过自反馈环路促进自我更新以及Serpine蛋白酶抑制剂的表达。通过抑制 caspase-1 和 cathepsin G，SERPINB6B 阻止 gasdermin D 介导的 pyroptosis（放纵性死亡）诱导。因此，SERPINB6B 抑制免疫原性细胞死亡，并通过其作用防止 T 细胞介导的肿瘤裂解。靶标抑制 Malat1 的药物治疗抗逆转录核苷酸抑制剂可以实现依赖 SERPINB6B 的抑制转移效果。这些结果提示，Malat1 导致的 SERPINB6B 表达能够平衡放纵性死亡和免疫识别在转移部位。因此，Malat1 介导肿瘤初始化、重编程以及免疫逃逸，它是一个具备处理潜力和临床相关性的药物靶点。