Alternative NF-kappa B signaling promotes colorectal tumorigenesis through transcriptionally upregulating Bcl-3
Alternative NF-kappa B signaling promotes colorectal tumorigenesis through transcriptionally upregulating Bcl-3
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替代性 NF-kappa B 信号通过转录上调 Bcl-3 促进结直肠肿瘤发生
DOI：
10.1038/s41388-018-0363-4
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发表时间：
2018
期刊：
影响因子：
8
通讯作者：
Zhang Xiaoren
中科院分区：
文献类型：
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作者：
Tao Yu;Liu Zhanjie;Hou Yingyong;Wang Shouli;Liu Sanhong;Jiang Yuhang;Tan Dan;Ge Qiulin;Li Cuifeng;Hu Yiming;Liu Zhi;Chen Xi;Wang Qi;Wang Mingliang;Zhang Xiaoren
多项研究表明，慢性炎症与结直肠癌的发生发展密切相关。经典的NF-κB信号是控制炎症的关键因素，已被发现在结直肠癌的发生发展中具有重要作用。然而，替代的NF-κB信号在结直肠癌中的作用仍然是未知的。在这里，我们发现在结直肠癌组织和结直肠癌细胞中，替代的NF-κB信号都有异常的结构性激活。Re B基因敲除可下调c-Myc，上调p27Kip1蛋白水平，从而抑制结直肠癌细胞增殖，延缓结直肠癌移植瘤生长。反之，过表达RelB会增加CRC细胞的增殖。此外，我们还发现在结直肠癌组织中，Bcl3和RelB之间存在显著的相关性。RelB的表达与Bcl3的表达及Bcl3下游蛋白p-Akt(S473)和p-GSK3β(S9)的磷酸化一致。Bcl3过表达可恢复RelB基因敲除引起的表型改变。重要的是，我们证明了替代性的NF-κB转录因子(P52：RelB)可以直接结合到Bcl3基因的启动子区域并上调其转录。此外，RelB、NF-κB2p52和Bcl3的表达与结直肠癌患者的生存不良有关。综上所述，这些结果表明，替代的NF-κB信号可能在结直肠癌中发挥致癌驱动作用，也为其他炎症性疾病的发病机制、预防和治疗提供了新的思路和研究方向。
Multiple studies have shown that chronic inflammation is closely related to the occurrence and development of colorectal cancer (CRC). Classical NF-κB signaling, the key factor in controlling inflammation, has been found to be of great importance to CRC development. However, the role of alternative NF-κB signaling in CRC is still elusive. Here, we found aberrant constitutive activation of alternative NF-κB signaling both in CRC tissue and CRC cells. Knockdown of RelB downregulates c-Myc and upregulates p27Kip1protein level, which inhibits CRC cell proliferation and retards CRC xenograft growth. Conversely, overexpression of RelB increases proliferation of CRC cells. In addition, we revealed a significant correlation between Bcl-3 and RelB in CRC tissues. The expression of RelB was consistent with the expression of Bcl-3 and the phosphorylation of Bcl-3 downstream proteins p-Akt (S473) and p-GSK3β (S9). Bcl-3 overexpression can restore the phenotype changes caused by RelB knockdown. Importantly, we demonstrated that alternative NF-κB transcriptional factor (p52:RelB) can directly bind to the promoter region ofBcl-3gene and upregulate its transcription. Moreover, the expression of RelB, NF-κB2 p52, and Bcl-3 was associated with poor survival of CRC patients. Taken together, these results represent that alternative NF-κB signaling may function as an oncogenic driver in CRC, and also provide new ideas and research directions for the pathogenesis, prevention, and treatment of other inflammatory-related diseases.