Université de Bordeaux, Bordeaux, France.
INSERM U1242, "Chemistry, Oncogenesis, Stress, Signaling", Université de Rennes 1, Rennes, France.
EMBO Mol Med. 2018 Mar;10(3). doi: 10.15252/emmm.201707929.
Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression.
蛋白质稳态失衡正成为癌症的一个主要特征，推动肿瘤侵袭性。有证据表明，内质网（ER）是蛋白质折叠和质量控制的主要场所，在癌症发展中起着关键作用。这一概念在多形性胶质母细胞瘤（GBM）中是有效的，GBM 是最致命的原发性脑癌，目前尚无有效的治疗方法。我们之前证明，内质网应激传感器 IRE1α（称为 IRE1）通过 XBP1 mRNA 剪接和调节 IRE1 依赖性衰减（RIDD）的 RNA 促进 GBM 的进展。在这里，我们首先证明了 IRE1 信号对人类 GBM 的重要性，并确定了特定的 IRE1 依赖性基因表达特征，这些特征与人类 GBM 转录组相对应。这种方法使我们能够证明 XBP1 mRNA 剪接和 RIDD 对肿瘤结局的拮抗作用，主要是通过选择性重塑肿瘤基质。这项研究首次证明了 IRE1 下游信号在癌症中的双重作用，并为阻断肿瘤进展开辟了新的治疗窗口。
