Liao Chaoliang, Li Min, Chen Xue, Tang Chenpeng, Quan Jing, Bode Ann M, Cao Ya, Luo Xiangjian
NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, PR China.
Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan, 410078, PR China.
J Exp Clin Cancer Res. 2023 Oct 7;42(1):261. doi: 10.1186/s13046-023-02835-6.
Epstein-Barr virus (EBV) is the first discovered human tumor virus that is associated with a variety of malignancies of both lymphoid and epithelial origin including nasopharyngeal carcinoma (NPC). The EBV-encoded latent membrane protein 1 (LMP1) has been well-defined as a potent oncogenic protein, which is intimately correlated with NPC pathogenesis. Anoikis is considered to be a physiological barrier to metastasis, and avoiding anoikis is a major hallmark of metastasis. However, the role of LMP1 in anoikis-resistance and metastasis of NPC has not been fully identified.
Trypan blue staining, colony formation assay, flow cytometry, and TUNEL staining, as well as the detection of apoptosis and anoikis resistance-related markers was applied to evaluate the anoikis-resistant capability of NPC cells cultured in ultra-low adhesion condition. Co-immunoprecipitation (Co-IP) experiment was performed to determine the interaction among LMP1, PRMT1 and PGC-1α. Ex vivo ubiquitination assay was used to detect the ubiquitination level of PGC-1α. Anoikis- resistant LMP1-positive NPC cell lines were established and applied for the xenograft and metastatic animal experiments.
Our current findings reveal the role of LMP1-stabilized peroxisome proliferator activated receptor coactivator-1a (PGC-1α) in anoikis resistance and immune escape to support the invasion and metastasis of NPC. Mechanistically, LMP1 enhances PGC-1α protein stability by promoting the interaction between arginine methyltransferase 1 (PRMT1) and PGC-1α to elevate the methylation modification of PGC-1α, thus endowing NPC cells with anoikis-resistance. Meanwhile, PGC-1α mediates the immune escape induced by LMP1 by coactivating with STAT3 to transcriptionally up-regulate PD-L1 expression.
Our work provides insights into how virus-encoded proteins recruit and interact with host regulatory elements to facilitate the malignant progression of NPC. Therefore, targeting PGC-1α or PRMT1-PGC-1α interaction might be exploited for therapeutic gain for EBV-associated malignancies.
爱泼斯坦-巴尔病毒（EBV）是首个被发现的人类肿瘤病毒，与多种淋巴源性和上皮源性恶性肿瘤相关，包括鼻咽癌（NPC）。EBV编码的潜伏膜蛋白1（LMP1）已被明确为一种强效致癌蛋白，与NPC发病机制密切相关。失巢凋亡被认为是转移的生理屏障，而避免失巢凋亡是转移的主要标志。然而，LMP1在NPC的失巢凋亡抵抗和转移中的作用尚未完全明确。
采用台盼蓝染色、集落形成试验、流式细胞术和TUNEL染色，以及检测凋亡和失巢凋亡抵抗相关标志物，评估在超低粘附条件下培养的NPC细胞的失巢凋亡抵抗能力。进行免疫共沉淀（Co-IP）实验以确定LMP1、蛋白精氨酸甲基转移酶1（PRMT1）和过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1α）之间的相互作用。采用体外泛素化试验检测PGC-1α的泛素化水平。建立失巢凋亡抵抗的LMP1阳性NPC细胞系，并应用于异种移植和转移动物实验。
我们目前的研究结果揭示了LMP1稳定的过氧化物酶体增殖物激活受体γ辅激活因子-1α（PGC-1α）在失巢凋亡抵抗和免疫逃逸中的作用，以支持NPC的侵袭和转移。机制上，LMP1通过促进精氨酸甲基转移酶1（PRMT1）与PGC-1α之间的相互作用来增强PGC-1α蛋白稳定性，从而提高PGC-1α的甲基化修饰，进而赋予NPC细胞失巢凋亡抵抗能力。同时，PGC-1α通过与信号转导和转录激活因子3（STAT3）共激活，转录上调程序性死亡受体配体1（PD-L1）表达，介导LMP1诱导的免疫逃逸。
我们的工作为病毒编码蛋白如何招募宿主调节元件并与之相互作用以促进NPC的恶性进展提供了见解。因此，靶向PGC-1α或PRMT1-PGC-1α相互作用可能为EBV相关恶性肿瘤带来治疗益处。
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