Li Mengna, Duan Yumei, Wei Jianxia, Chen Shipeng, Xue Changning, Zheng Lemei, Deng Hongyu, Fan Songqing, Xiong Wei, Li Guiyuan, Tan Ming, Tang Faqing, She Kelin, Zhou Ming
NHC Key Laboratory of Carcinogenesis, Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University Changsha 410078, Hunan, China.
Cancer Research Institute and School of Basic Medical Sciences, Central South University Changsha 410078, Hunan, China.
Am J Cancer Res. 2023 Aug 15;13(8):3763-3780. eCollection 2023.
Tumor metastasis is a leading cause of death in nasopharyngeal carcinoma (NPC) patients. Previous research has identified that transcription factor Yin Yang 1 (YY1) acts as a tumor suppressor that inhibits cell proliferation and tumor growth in NPC; however, the role and the molecular mechanisms of YY1 in NPC invasion and metastasis remain unclear. In this study, we discovered that YY1 could inhibit the migration and invasion of NPC cells in vitro as well as NPC xenograft tumor metastasis in vivo. Furthermore, we identified eIF4E as a direct downstream target of YY1, and YY1 could negatively regulate the expression of eIF4E at transcriptional level. Moreover, we found that eIF4E promoted the migration and invasion of NPC cells as well as NPC lung metastasis, suggesting its potential as a pro-metastatic mediator in NPC. Importantly, restoring eIF4E expression could partially reverse the inhibitory effects of YY1 on NPC malignancy. In consistent with these findings, the expression of YY1 was downregulated while eIF4E was upregulated in NPC patients with metastasis, and there was a negative correlation between YY1 and eIF4E expression. Collectively, our results indicate that YY1 suppresses the invasion and metastasis of NPC by negatively regulating eIF4E transcription. Therefore, targeting the YY1/eIF4E transcriptional axis could be a potential therapeutic strategy for the treatment of patients with NPC.
肿瘤转移是鼻咽癌（NPC）患者死亡的主要原因。先前的研究已经确定转录因子阴阳1（YY1）作为一种肿瘤抑制因子，可抑制NPC中的细胞增殖和肿瘤生长；然而，YY1在NPC侵袭和转移中的作用及分子机制仍不清楚。在本研究中，我们发现YY1在体外可抑制NPC细胞的迁移和侵袭以及体内NPC异种移植瘤的转移。此外，我们确定真核翻译起始因子4E（eIF4E）是YY1的直接下游靶点，并且YY1可在转录水平负调控eIF4E的表达。而且，我们发现eIF4E促进NPC细胞的迁移和侵袭以及NPC肺转移，表明其在NPC中作为促转移介质的潜力。重要的是，恢复eIF4E表达可部分逆转YY1对NPC恶性程度的抑制作用。与这些发现一致，在发生转移的NPC患者中YY1表达下调而eIF4E表达上调，并且YY1与eIF4E表达之间存在负相关。总体而言，我们的结果表明YY1通过负调控eIF4E转录来抑制NPC的侵袭和转移。因此，靶向YY1/eIF4E转录轴可能是治疗NPC患者的一种潜在治疗策略。
