Epstein-Barr Virus-Encoded Latent Membrane Protein 2A Promotes the Epithelial-Mesenchymal Transition in Nasopharyngeal Carcinoma via Metastatic Tumor Antigen 1 and Mechanistic Target of Rapamycin Signaling Induction

Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) promotes the epithelial-mesenchymal transition (EMT) of nasopharyngeal carcinoma (NPC), thereby increasing tumor invasion. Recently, the dysregulation of metastatic tumor antigen 1 (MTA1) was found to enhance tumor metastasis in a variety of cancers. A molecular connection between these two proteins has been proposed but not firmly established. In this study, we reported the overexpression of MTA1 in 29/60 (48.3%) NPC patients, and the overexpression of MTA1 significantly correlated with tumor metastasis. The overexpression of MTA1 promoted EMT via the Wnt1 pathway and beta-catenin activation. We demonstrated that LMP2A reinforces the expression of MTA1 via the mechanistic target of rapamycin (mTOR) pathway to promote EMT in NPC. Furthermore, by knocking down 4EBP1 in combination with the new mTOR inhibitor INK-128 treatment, we discovered that LMP2A expression activates the 4EBP1-eIF4E axis and increases the expression of MTA1 at the translational level partially independent of c-myc. These findings provided novel insights into the correlation between the LMP2A and MTA1 proteins and reveal a novel function of the 4EBP1-eIF4E axis in EMT of nasopharyngeal carcinoma.IMPORTANCEPrevention of the recurrence and metastasis of NPC is critical to achieving a successful NPC treatment. As we all know, EMT has a vital role in metastasis of malignancies. LMP2A, an oncoprotein of Epstein-Barr virus, a well-known NPC activator, induces EMT and has been proved to exert a promoting effect in tumor metastasis. Our study demonstrated that LMP2A could induce EMT by activating MTA1 at the translational level via activating mTOR signaling and the 4EBP1-eIF4E axis. Taken together, our findings bridge the gap between the NPC-specific cell surface molecule and the final phenotype of the NPC cells. Additionally, our findings indicate that LMP2A and mTOR will serve as targets for NPC therapy in the future.

爱泼斯坦 - 巴尔病毒编码的潜伏膜蛋白2A（LMP2A）促进鼻咽癌（NPC）的上皮 - 间质转化（EMT），从而增加肿瘤侵袭性。近期，发现转移肿瘤抗原1（MTA1）的失调会增强多种癌症的肿瘤转移。已提出这两种蛋白质之间存在分子联系，但尚未确定。在本研究中，我们报道在60例鼻咽癌患者中有29例（48.3%）MTA1过表达，且MTA1过表达与肿瘤转移显著相关。MTA1过表达通过Wnt1通路和β - 连环蛋白激活促进EMT。我们证明LMP2A通过雷帕霉素靶蛋白（mTOR）通路增强MTA1的表达，从而促进鼻咽癌中的EMT。此外，通过联合敲低4EBP1以及使用新型mTOR抑制剂INK - 128治疗，我们发现LMP2A表达激活4EBP1 - eIF4E轴，并在翻译水平上增加MTA1的表达，且部分不依赖于c - myc。这些发现为LMP2A和MTA1蛋白之间的相关性提供了新的见解，并揭示了4EBP1 - eIF4E轴在鼻咽癌EMT中的新功能。 重要性 预防鼻咽癌的复发和转移对于成功治疗鼻咽癌至关重要。众所周知，EMT在恶性肿瘤的转移中起着至关重要的作用。LMP2A是爱泼斯坦 - 巴尔病毒的一种癌蛋白，是众所周知的鼻咽癌激活因子，可诱导EMT，并已被证明在肿瘤转移中起促进作用。我们的研究表明，LMP2A可通过激活mTOR信号通路和4EBP1 - eIF4E轴在翻译水平上激活MTA1来诱导EMT。综上所述，我们的发现弥合了鼻咽癌特异性细胞表面分子与鼻咽癌细胞最终表型之间的差距。此外，我们的发现表明LMP2A和mTOR将成为未来鼻咽癌治疗的靶点。