Suppression of CCDC6 sensitizes tumor to oncolytic virus M1.
Suppression of CCDC6 sensitizes tumor to oncolytic virus M1.
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抑制 CCDC6 使肿瘤对溶瘤病毒 M1 敏感
DOI：
10.1016/j.neo.2020.12.003
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Hu C
中科院分区：
文献类型：
--
作者：
Liu Y;Li K;Zhu WB;Zhang H;Huang WT;Liu XC;Lin Y;Cai J;Yan GM;Qiu JG;Peng L;Liang JK;Hu C
溶瘤病毒是一种有效的肿瘤治疗策略，它利用天然或人工操纵的病毒选择性地靶向和杀伤癌细胞。然而，癌细胞的先天性抗病毒系统可能对溶瘤病毒的治疗产生抗性。M1病毒是一种新发现的溶瘤病毒，属于甲病毒属，但其抗癌活性的分子机制在很大程度上是未知的。通过3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四唑（MTT）测定来测量细胞活力。RNA测序分析M1病毒感染后的基因变化。用于基因敲低的小干扰RNA转染用于基因功能测试。Caspase-3/7活性采用Caspase-Glo Assay Systems检测。建立小鼠原位膀胱肿瘤模型以确定M1病毒的溶瘤效力。免疫组化法检测肿瘤细胞中Caspase 3和Ki-67的表达。为了进一步确定M1病毒介导的生物学功能中涉及的分子因素，我们敲除了与甲病毒活性相关的基因，发现CCDC 6在M1病毒的溶瘤活性中起重要作用。此外，CCDC 6的敲低增强了M1病毒的繁殖，并导致内质网（ER）应激诱导的细胞凋亡在体外以及在体内原位膀胱癌模型。我们的研究为开发新的化合物以提高溶瘤病毒治疗的功效提供了合理的新靶点。
Oncolytic virus is an effective therapeutic strategy for cancer treatment, which exploits natural or manipulated viruses to selectively target and kill cancer cells. However, the innate antiviral system of cancer cells may resistant to the treatment of oncolytic virus. M1 virus is a newly identified oncolytic virus belonging to alphavirus species, but the molecular mechanisms underlying its anticancer activity are largely unknown. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays. RNA seq analysis was used to analyze the gene alternation after M1 virus infection. Small interfering RNAs transfection for gene knockdown was used for gene functional tests. Caspase-3/7 activity was detected by Caspase-Glo Assay Systems. A mice model of orthotopic bladder tumor was established to determine the oncolytic effectiveness of the M1 virus. The expression of cleaved-Caspase 3 as well as Ki-67 in tumor cells were detected by immunohistochemical analysis. To further define the molecular factors involved in M1 virus-mediated biological function, we knocked down genes related to alphavirus’ activity and found that CCDC6 plays an important role in the oncolytic activity of M1 virus. Moreover, knocked down of CCDC6 augments the reproduction of M1 virus and resulted in endoplasmic reticulum (ER) stress-induced cell apoptosis in vitro as well as in vivo orthotopic bladder cancer model. Our research provides a rational new target for developing new compounds to promote the efficacy of oncolytic virus therapy.
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