Li Zhilan, Zhou Zhuan, Wu Xia, Zhou Qin, Liao Chaoliang, Liu Ying, Li Dan, Shen Liangfang, Feng Deyun, Yang Lifang
Department of Oncology, Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Xiangya Hospital, Central South University Changsha, China.
Cancer Research Institute, School of Basic Medicine Science, Central South University Changsha, China.
Am J Cancer Res. 2020 Jul 1;10(7):2083-2099. eCollection 2020.
Anoikis resistance is an important mechanism that mediates tumor metastasis. Studies have found that Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) promotes the occurrence, development, and metastasis of nasopharyngeal carcinoma (NPC). However, the related mechanism, especially whether LMP1 is involved in NPC metastasis through anoikis resistance, has not yet been elucidated. In present study, we showed that LMP1 enhanced the ability of NPC cells to resist anoikis by upregulating neurotrophic tyrosine kinase receptor type 2 (NTRK2 or TrkB) expression through NF-κB signaling and promoted the migration and invasion of NPC cells. After knockdown of NTRK2, the p-ERK and p-AKT in NPC cells were inhibited, and twist expression was further reduced, resulting in upregulation of E-cadherin expression and downregulation of vimentin expression. Subsequently, the results of a xenograft experiment showed that inhibiting NTRK2 could reduce LMP1-mediated NPC metastasis in vivo. In summary, these findings demonstrated that EBV-LMP1 upregulates twist expression to promote epithelial-mesenchymal transition (EMT) through the NTRK2-mediated AKT/ERK signaling pathway, thus mediating anoikis resistance and promoting NPC metastasis. These data will provide new molecular markers and potential targets for NPC metastasis.
失巢凋亡抗性是介导肿瘤转移的重要机制。研究发现，爱泼斯坦-巴尔病毒（EBV）编码的潜伏膜蛋白1（LMP1）促进鼻咽癌（NPC）的发生、发展和转移。然而，相关机制，尤其是LMP1是否通过失巢凋亡抗性参与NPC转移，尚未阐明。在本研究中，我们发现LMP1通过NF-κB信号上调神经营养酪氨酸激酶受体2（NTRK2或TrkB）的表达，增强NPC细胞抵抗失巢凋亡的能力，并促进NPC细胞的迁移和侵袭。敲低NTRK2后，NPC细胞中的p-ERK和p-AKT受到抑制，twist表达进一步降低，导致E-钙黏蛋白表达上调，波形蛋白表达下调。随后，异种移植实验结果表明，抑制NTRK2可在体内减少LMP1介导的NPC转移。总之，这些发现表明，EBV-LMP1通过NTRK2介导的AKT/ERK信号通路上调twist表达，促进上皮-间质转化（EMT），从而介导失巢凋亡抗性并促进NPC转移。这些数据将为NPC转移提供新的分子标志物和潜在靶点。
