Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, Guangdong, PR China; Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, Southern Medical University, Guangzhou 510515, Guangdong, PR China.
Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou 510515, Guangdong, PR China; Key Laboratory of Antibody Engineering of Guangdong Higher Education Institutes, Southern Medical University, Guangzhou 510515, Guangdong, PR China; Department of Gynecology and Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou 510000, Guangdong, PR China.
Life Sci. 2022 Feb 15;291:120297. doi: 10.1016/j.lfs.2021.120297. Epub 2022 Jan 8.
Orf virus (ORFV) is a parapoxvirus causing contagious ecthyma in sheep and goats. With inhibitory role of ORFV reported by previous studies, ORFV can be a candidate of oncolytic virus. However, few studies reported the application and mechanism of ORFV in nasopharyngeal carcinoma (NPC). We aimed to elucidate the anti-tumor mechanism of ORFV against NPC cells.
The anti-tumor effect of ORFV in NPC cells was confirmed by cell counting kit 8 (CCK-8) assay, flow cytometry and Western blot. In vitro and in vivo experiments were adopted to evaluate the inhibitory effect of ORFV in NPC cells. Western blot was used to determine the down-regulation of rapamycin (mTOR) signaling and autophagy enhancement induced by ORFV. To explore the mechanism of ORFV on NPC cells, mTOR signaling agonist and autophagy inhibitors were used to rescue the effects of ORFV.
The results indicated that ORFV replicates in NPC cells, thus induces the apoptosis of NPC cells. Moreover, ORFV can effectively inhibit NPC cell growth in vivo. ORFV infection in NPC cells leads to the mTOR signaling inhibition and up-regulated autophagy, which might be the specific mechanism of ORFV in killing tumor cells. As to safety confirmation, normal nasopharyngeal epithelial cells NP69 are insensitive to ORFV. More importantly, ORFV would not cause organ damage in vivo.
Our data clarified that ORFV induces autophagy of NPC cells via inhibiting mTOR signaling, thus further inducing apoptosis. The anti-tumor role of ORFV might provide a preclinical strategy for NPC treatment.
口疮病毒（ORFV）是一种引起绵羊和山羊传染性脓疱的副痘病毒。既往研究报道 ORFV 具有抑制作用，因此 ORFV 可以作为溶瘤病毒的候选者。然而，鲜有研究报道 ORFV 在鼻咽癌（NPC）中的应用及机制。本研究旨在阐明 ORFV 针对 NPC 细胞的抗肿瘤机制。
通过细胞计数试剂盒 8（CCK-8）检测、流式细胞术和 Western blot 证实 ORFV 在 NPC 细胞中的抗肿瘤作用。采用体外和体内实验评估 ORFV 对 NPC 细胞的抑制作用。Western blot 用于确定 ORFV 诱导的 rapamycin（mTOR）信号下调和自噬增强。为了探讨 ORFV 对 NPC 细胞的作用机制，使用 mTOR 信号激动剂和自噬抑制剂来挽救 ORFV 的作用。
结果表明 ORFV 在 NPC 细胞中复制，从而诱导 NPC 细胞凋亡。此外，ORFV 可有效抑制 NPC 细胞在体内的生长。ORFV 感染 NPC 细胞导致 mTOR 信号抑制和自噬上调，这可能是 ORFV 杀伤肿瘤细胞的特定机制。为了确认安全性，正常鼻咽上皮细胞 NP69对 ORFV 不敏感。更为重要的是，ORFV 在体内不会引起器官损伤。
本研究数据阐明了 ORFV 通过抑制 mTOR 信号诱导 NPC 细胞自噬，从而进一步诱导细胞凋亡。ORFV 的抗肿瘤作用可能为 NPC 治疗提供一种临床前策略。
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