State Key Laboratory of Oncology in South China, Sun Yat-sen Universitygrid.12981.33 Cancer Center, Guangzhou, China.
Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen Universitygrid.12981.33, Guangzhou, Guangdong, China.
J Virol. 2022 Mar 9;96(5):e0194121. doi: 10.1128/jvi.01941-21. Epub 2022 Jan 12.
Epstein-Barr virus (EBV) is associated with several malignant diseases, including Burkitt's lymphoma, nasopharyngeal carcinoma (NPC), certain types of lymphomas, and a portion of gastric cancers. The virus-encoded oncoprotein, LMP1, induces the epithelial-to-mesenchymal transition (EMT), leading to cancer stem cell formation. In the current study, we investigated how LMP1 contributes to cancer stem cell development in NPC. We found that LMP1 plays an essential role in acquiring cancer stem cell (CSC) characteristics, including tumor initiation, metastasis, and therapeutic resistance by activating the PI3K/mTOR/Akt signaling pathway. We dissected the functions of distinct signaling (mTORC1 and mTORC2) in the acquisition of different CSC characteristics. Side population (SP) formation, which represents the chemotherapy resistance feature of CSC, requires mTORC1 signaling. Tumor initiation capability is mainly attributed to mTORC2, which confers on NPC the capabilities of proliferation and survival by activating mTORC2 downstream genes c-Myc. Both mTORC1 and mTORC2 enhance cell migration and invasion of NPC cells, suggesting that mTORC1/2 coregulate metastasis of NPC. The revelation of the roles of the mTOR signaling pathways in distinct tumorigenic features provides a guideline for designing efficient therapies by choosing specific mTOR inhibitors targeting mTORC1, mTORC2, or both to achieve durable remission of NPC in patients. LMP1 endows NPC to gain cancer stem cell characteristics through activating mTORC1 and mTORC2 pathways. The different mTOR pathways are responsible for distinct tumorigenic features. Rapamycin-insensitive mTORC1 is essential for CSC drug resistance. NPC tumor initiation capacity is mainly attributed to mTORC2 signaling. mTORC1 and mTORC2 coregulate NPC cell migration and invasion. The revelation of the roles of mTOR signaling in NPC CSC establishment has implications for novel therapeutic strategies to treat relapsed and metastatic NPC and achieve durable remission.
EB 病毒（EBV）与多种恶性疾病相关，包括伯基特淋巴瘤、鼻咽癌（NPC）、某些类型的淋巴瘤和部分胃癌。病毒编码的癌蛋白 LMP1 诱导上皮-间充质转化（EMT），导致癌症干细胞的形成。在本研究中，我们研究了 LMP1 如何促进 NPC 中的癌症干细胞的发展。我们发现，LMP1 通过激活 PI3K/mTOR/Akt 信号通路，在获得癌症干细胞（CSC）特征方面发挥重要作用，包括肿瘤起始、转移和治疗抵抗。我们剖析了不同信号（mTORC1 和 mTORC2）在获得不同 CSC 特征中的作用。侧群（SP）形成，代表 CSC 的化疗耐药特征，需要 mTORC1 信号。肿瘤起始能力主要归因于 mTORC2，它通过激活 mTORC2 下游基因 c-Myc 赋予 NPC 增殖和存活的能力。mTORC1 和 mTORC2 均增强 NPC 细胞的迁移和侵袭能力，表明 mTORC1/2 共同调节 NPC 的转移。mTOR 信号通路在不同肿瘤发生特征中的作用的揭示为设计通过选择针对 mTORC1、mTORC2 或两者的特定 mTOR 抑制剂的有效治疗方法提供了指导，以实现 NPC 患者的持久缓解。LMP1 通过激活 mTORC1 和 mTORC2 途径赋予 NPC 获得癌症干细胞特征。不同的 mTOR 途径负责不同的肿瘤发生特征。雷帕霉素不敏感的 mTORC1 对于 CSC 耐药至关重要。NPC 肿瘤起始能力主要归因于 mTORC2 信号。mTORC1 和 mTORC2 共同调节 NPC 细胞的迁移和侵袭。mTOR 信号在 NPC CSC 建立中的作用的揭示为治疗复发性和转移性 NPC 并实现持久缓解的新治疗策略提供了意义。
