Giunco Silvia, Petrara Maria Raffaella, Zangrossi Manuela, Celeghin Andrea, De Rossi Anita
1Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto (IOV)-IRCCS, Padova, Italy.
2Department of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, University of Padova, Padova, Italy.
Infect Agent Cancer. 2018 Apr 10;13:14. doi: 10.1186/s13027-018-0186-5. eCollection 2018.
The Epstein-Barr virus (EBV) is a ubiquitous human γ-herpesvirus causally linked to a broad spectrum of both lymphoid and epithelial malignancies. In order to maintain its persistence in host cells and promote tumorigenesis, EBV must restrict its lytic cycle, which would ultimately lead to cell death, selectively express latent viral proteins, and establish an unlimited proliferative potential. The latter step depends on the maintenance of telomere length provided by telomerase. The viral oncoprotein LMP-1 activates TERT, the catalytic component of telomerase. In addition to its canonical role in stabilizing telomeres, TERT may promote EBV-driven tumorigenesis through extra-telomeric functions. TERT contributes toward preserving EBV latency; in fact, through the NOTCH2/BATF pathway, TERT negatively affects the expression of BZLF1, the master regulator of the EBV lytic cycle. In contrast, TERT inhibition triggers a complete EBV lytic cycle, leading to the death of EBV-infected cells. Interestingly, short-term TERT inhibition causes cell cycle arrest and apoptosis, partly by inducing telomere-independent activation of the ATM/ATR/TP53 pathway. Importantly, TERT inhibition also sensitizes EBV-positive tumor cells to antiviral therapy and enhances the pro-apoptotic effects of chemotherapeutic agents. We provide here an overview on how the extra-telomeric functions of TERT contribute to EBV-driven tumorigenesis. We also discuss the potential therapeutic approach of TERT inhibition in EBV-driven malignancies.
爱泼斯坦-巴尔病毒（EBV）是一种普遍存在的人类γ疱疹病毒，与多种淋巴和上皮恶性肿瘤存在因果关联。为了在宿主细胞中维持其持续性并促进肿瘤发生，EBV必须限制其裂解周期（这最终会导致细胞死亡），选择性表达潜伏性病毒蛋白，并建立无限增殖潜能。后一步骤取决于端粒酶提供的端粒长度维持。病毒癌蛋白LMP-1激活端粒酶的催化成分TERT。除了在稳定端粒方面的经典作用外，TERT可能通过端粒外功能促进EBV驱动的肿瘤发生。TERT有助于维持EBV潜伏状态；事实上，通过NOTCH2/BATF途径，TERT会负面影响EBV裂解周期的主要调节因子BZLF1的表达。相反，TERT抑制会触发完整的EBV裂解周期，导致EBV感染细胞死亡。有趣的是，短期TERT抑制会导致细胞周期停滞和凋亡，部分原因是诱导ATM/ATR/TP53途径的端粒非依赖性激活。重要的是，TERT抑制还会使EBV阳性肿瘤细胞对抗病毒治疗敏感，并增强化疗药物的促凋亡作用。我们在此概述TERT的端粒外功能如何促进EBV驱动的肿瘤发生。我们还讨论了TERT抑制在EBV驱动的恶性肿瘤中的潜在治疗方法。
