Zhu Mengying, Wang Yilong, Qu Chufan, Liu Rongxian, Zhang Chudi, Wang Jinhu, Zhou Dongming, Gu Weizhong, Chen Peichun, Wu Benqing, Zhao Zhengyan
Zhejiang University School of Medicine Hangzhou, Zhejiang, China.
Children's Hospital, Zhejiang University School of Medicine Hangzhou 310052, Zhejiang, China.
Am J Transl Res. 2021 Apr 15;13(4):2077-2093. eCollection 2021.
In previous studies oncolytic measles viruses (MVs) have shown significant antitumor activity against various tumors. In our research recombinant MV-Hu191 (rMV-Hu191), established via reverse genetics technology and expressing enhanced green fluorescent protein (EGFP), was evaluated for its therapeutic effects and related mechanisms against nephroblastoma cell lines. We built three different constructs based on rMV-Hu191 to express EGFP effectively. Our experiments showed that rMV-Hu191 expressing EGFP could efficiently infect and replicate in nephroblastoma cell lines. Caspase-induced apoptosis exerted a significant impact on MV-induced cell death, which was accompanied by emission of cellular ATP and high-mobility group protein 1 (HMGB1) and by translocation of calreticulin (CRT). Intratumoral injection of rMV-Hu191-EGFP resulted in significant regression of tumors in a G401 xenograft model. Our results indicate that the MV-Hu191 strain, which is widely used in China, is an appropriate vector for expression of foreign genes and could serve as a potentially good candidate for nephroblastoma therapy mediated by induction of apoptosis-associated immunogenic cell death (ICD).
在以往的研究中,溶瘤麻疹病毒(MVs)已显示出对多种肿瘤具有显著的抗肿瘤活性。在我们的研究中,通过反向遗传学技术构建并表达增强型绿色荧光蛋白(EGFP)的重组MV-Hu191(rMV-Hu191),对其针对肾母细胞瘤细胞系的治疗效果及相关机制进行了评估。我们基于rMV-Hu191构建了三种不同的构建体以有效表达EGFP。我们的实验表明,表达EGFP的rMV-Hu191能够在肾母细胞瘤细胞系中高效感染和复制。半胱天冬酶诱导的凋亡对MV诱导的细胞死亡产生了显著影响,这伴随着细胞ATP和高迁移率族蛋白1(HMGB1)的释放以及钙网蛋白(CRT)的转位。瘤内注射rMV-Hu191-EGFP导致G401异种移植模型中的肿瘤显著消退。我们的结果表明,在中国广泛使用的MV-Hu191株是一种适合表达外源基因的载体,并且可能作为通过诱导凋亡相关免疫原性细胞死亡(ICD)介导的肾母细胞瘤治疗的潜在良好候选者。