Oncogenic Fusion Gene CD74-NRG1 Confers Cancer Stem Cell-like Properties in Lung Cancer through a IGF2 Autocrine/Paracrine Circuit
Oncogenic Fusion Gene CD74-NRG1 Confers Cancer Stem Cell-like Properties in Lung Cancer through a IGF2 Autocrine/Paracrine Circuit
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DOI：
10.1158/0008-5472.can-15-2135
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发表时间：
2016-02-15
期刊：
影响因子：
11.2
通讯作者：
Gotoh, Noriko
中科院分区：
文献类型：
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作者：
Murayama, Takahiko;Nakaoku, Takashi;Gotoh, Noriko
CD 74-Neuregulin 1（NRG 1）融合基因最近被鉴定为侵袭性粘液腺癌（一种恶性形式的肺癌）的新驱动因子。然而，CD 74-NRG 1融合基因在腺癌发病机制中的功能及其可能赋予癌症干细胞（CSC）促肿瘤发生特性的机制仍不清楚。在这项研究中，我们发现CD 74-NRG 1融合基因的表达增加了具有CSC样特性的肺癌细胞的数量。CD 74-NRG 1表达不仅促进癌细胞的球体形成，而且促进非恶性肺上皮细胞的球体形成。在异种移植模型中使用有限稀释测定，我们进一步表明CD 74-NRG 1融合基因增强肿瘤起始。在机制上，我们发现CD 74-NRG 1的表达促进ErbB 2/3的磷酸化，激活PI 3 K/Akt/NF-κ B信号通路。此外，在表达CD 74-NRG 1的细胞中，分泌的胰岛素样生长因子2（IGF 2）的表达及其受体IGF 1 R的磷酸化以NF-κ B依赖性方式增强。这些发现表明，CD 74-NRG 1诱导的NF-κ B活性促进IGF 2自分泌/旁分泌回路。此外，抑制ErbB 2、PI 3 K、NF-κ B或IGF 2可抑制CD 74-NRG 1诱导的肿瘤球形成。因此，我们的研究提供了一个临床前的理由，开发基于这些确定的途径，以抑制CSC的属性，促进肿瘤进展和复发的治疗方法。(C)2016年AACR。
The CD74-Neuregulin1 (NRG1) fusion gene was recently identified as novel driver of invasive mucinous adenocarcinoma, a malignant form of lung cancer. However, the function of the CD74-NRG1 fusion gene in adenocarcinoma pathogenesis and the mechanisms by which it may impart protumorigenic characteristics to cancer stem cells (CSC) is still unclear. In this study, we found that the expression of the CD74-NRG1 fusion gene increased the population of lung cancer cells with CSC-like properties. CD74-NRG1 expression facilitated sphere formation not only of cancer cells, but also of nonmalignant lung epithelial cells. Using a limiting dilution assay in a xenograft model, we further show that the CD74-NRG1 fusion gene enhanced tumor initiation. Mechanistically, we found that CD74-NRG1 expression promoted the phosphorylation of ErbB2/3 and activated the PI3K/Akt/NF-kappa B signaling pathway. Furthermore, the expression of the secreted insulin-like growth factor 2 (IGF2) and phosphorylation of its receptor, IGF1R, were enhanced in an NF-kappa B-dependent manner in cells expressing CD74-NRG1. These findings suggest that CD74-NRG1-induced NF-kappa B activity promotes the IGF2 autocrine/paracrine circuit. Moreover, inhibition of ErbB2, PI3K, NF-kappa B, or IGF2 suppressed CD74-NRG1-induced tumor sphere formation. Therefore, our study provides a preclinical rationale for developing treatment approaches based on these identified pathways to suppress CSC properties that promote tumor progression and recurrence. (C) 2016 AACR.