Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China.
Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, University of South China, Hengyang, China.
Cell Prolif. 2018 Oct;51(5):e12464. doi: 10.1111/cpr.12464. Epub 2018 Jul 13.
β-catenin is one of the most critical oncogenes associated with many kinds of human cancers, especially in the human CRC. Innate immunity recognizes tumour derived damage-associated molecular patterns (DAMPs) and primes the anti-tumour adaptive responses. While the function of β-catenin in CRC tumourigenesis is well established, its impact on innate immune evasion is largely unknown. The aim of this study is to characterize the role of β-catenin in inhibiting RIG-I-like receptor (RLR)-mediated IFN-β signalling in colorectal cancer.
Immunohistochemical staining and western blotting were conducted to study the expression of β-catenin, IRF3 and phospho-IRF3 (p-IRF3) in CRC samples and cell lines. Plaque assay determining virus replication was performed to assess the regulation of β-catenin on IFN-β signalling. The inhibition of β-catenin on RLR-mediated IFN-β signalling was further studied by real-time analyses and reporter assays in the context of lentiviral-mediated β-catenin stably knocking down. Lastly, co-immunoprecipitation and nuclear fractionation assay were conducted to monitor the interaction between β-catenin and IRF3.
We found that high expression of β-catenin positively correlated with the expression of IRF3 in CRC cells. Overexpression of β-catenin increased the viral replication. Conversely knocking down of β-catenin inhibited viral replication. Furthermore, our data demonstrated that β-catenin could inhibit the expression of IFN-β and interferon-stimulated gene 56 (ISG56). Mechanistically, we found that β-catenin interacted with IRF3 and blocked its nuclear translocation.
Our study reveals an unprecedented role of β-catenin in enabling innate immune evasion in CRC.
β-连环蛋白是与多种人类癌症相关的最关键的癌基因之一，尤其在人结直肠癌（CRC）中。固有免疫识别肿瘤来源的损伤相关分子模式（DAMPs）并启动抗肿瘤适应性反应。虽然β-连环蛋白在 CRC 肿瘤发生中的作用已得到充分证实，但它对固有免疫逃避的影响在很大程度上尚不清楚。本研究旨在探讨β-连环蛋白在抑制结直肠癌细胞中 RIG-I 样受体（RLR）介导的 IFN-β 信号通路中的作用。
通过免疫组织化学染色和 Western blot 分析研究 CRC 样本和细胞系中β-连环蛋白、IRF3 和磷酸化 IRF3（p-IRF3）的表达。通过测定病毒复制的噬斑试验评估β-连环蛋白对 IFN-β 信号通路的调节。通过实时分析和报告基因分析进一步研究β-连环蛋白在慢病毒介导的β-连环蛋白稳定敲低背景下对 RLR 介导的 IFN-β 信号通路的抑制作用。最后，通过共免疫沉淀和核质分离实验监测β-连环蛋白与 IRF3 之间的相互作用。
我们发现β-连环蛋白的高表达与 CRC 细胞中 IRF3 的表达呈正相关。β-连环蛋白的过表达增加了病毒的复制。相反，β-连环蛋白的敲低抑制了病毒的复制。此外，我们的数据表明β-连环蛋白可以抑制 IFN-β 和干扰素刺激基因 56（ISG56）的表达。机制上，我们发现β-连环蛋白与 IRF3 相互作用并阻止其核转位。
本研究揭示了β-连环蛋白在 CRC 中固有免疫逃避中的一个前所未有的作用。
