Institut National de la Santé et de la Recherche Médicale (Inserm), LNC UMR1231, LabEx LIpSTIC, Team with the label of excellence from «la ligue national contre le Cancer», 21000, Dijon, France.
Université de Bourgogne-Franche-Comté, 21000, Dijon, France.
Oncogene. 2023 Jan;42(3):198-208. doi: 10.1038/s41388-022-02544-y. Epub 2022 Nov 18.
Cellular inhibitor of apoptosis-1 (cIAP1) is a signaling regulator with oncogenic properties. It is involved in the regulation of signaling pathways controlling inflammation, cell survival, proliferation, differentiation and motility. It is recruited into membrane-receptor-associated signaling complexes thanks to the molecular adaptor TRAF2. However, the cIAP1/TRAF2 complex exists, independently of receptor engagement, in several subcellular compartments. The present work strengthens the importance of TRAF2 in the oncogenic properties of cIAP1. cIAPs-deficient mouse embryonic fibroblasts (MEFs) were transformed using the HRas-V12 oncogene. Re-expression of cIAP1 enhanced tumor growth in a nude mice xenograft model, and promoted lung tumor nodes formation. Deletion or mutation of the TRAF2-binding site completely abolished the oncogenic properties of cIAP1. Further, cIAP1 mediated the clustering of TRAF2, which was sufficient to stimulate tumor growth. Our TRAF2 interactome analysis showed that cIAP1 was critical for TRAF2 to bind to its protein partners. Thus, cIAP1 and TRAF2 would be two essential subunits of a signaling complex promoting a pro-tumoral signal. cIAP1/TRAF2 promoted the activation of the canonical NF-κB and ERK1/2 signaling pathways. NF-κB-dependent production of IL-6 triggered the activation of the JAK/STAT3 axis in an autocrine manner. Inhibition or downregulation of STAT3 specifically compromised the growth of cIAP1-restored MEFs but not that of MEFs expressing a cIAP1-mutant and treating mice with the STAT3 inhibitor niclosamide completely abrogated cIAP1/TRAF2-mediated tumor growth. Altogether, we demonstrate that cIAP1/TRAF2 binding is essential to promote tumor growth via the activation of the JAK/STAT3 signaling pathway.
细胞凋亡抑制因子 1（cIAP1）是一种具有致癌特性的信号调节因子。它参与调节控制炎症、细胞存活、增殖、分化和运动的信号通路。它通过分子接头 TRAF2 被募集到膜受体相关信号复合物中。然而，cIAP1/TRAF2 复合物独立于受体结合，存在于几个亚细胞隔室中。本研究工作加强了 TRAF2 在 cIAP1 致癌特性中的重要性。使用 HRas-V12 癌基因转化 cIAPs 缺陷型小鼠胚胎成纤维细胞（MEFs）。cIAP1 的重新表达增强了裸鼠异种移植模型中的肿瘤生长，并促进了肺肿瘤节点的形成。TRAF2 结合位点的缺失或突变完全消除了 cIAP1 的致癌特性。此外，cIAP1 介导了 TRAF2 的聚集，这足以刺激肿瘤生长。我们的 TRAF2 相互作用组分析表明，cIAP1 对于 TRAF2 与其蛋白伴侣结合至关重要。因此，cIAP1 和 TRAF2 将是促进促肿瘤信号的信号复合物的两个必需亚基。cIAP1/TRAF2 促进了经典 NF-κB 和 ERK1/2 信号通路的激活。NF-κB 依赖性的 IL-6 产生以自分泌方式触发 JAK/STAT3 轴的激活。STAT3 的抑制或下调特异性损害了 cIAP1 恢复的 MEFs 的生长，但不损害表达 cIAP1 突变体的 MEFs 的生长，并且用 STAT3 抑制剂尼洛替尼治疗小鼠完全消除了 cIAP1/TRAF2 介导的肿瘤生长。总之，我们证明了 cIAP1/TRAF2 结合对于通过激活 JAK/STAT3 信号通路促进肿瘤生长是必不可少的。
