The Oncolytic Activity of Myxoma Virus against Soft Tissue Sarcoma Is Mediated by the Overexpression of Ribonucleotide Reductase,Clinical Medicine Insights: Oncology

当前位置： X-MOL 学术 › Clin. Med. Insights Oncol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

The Oncolytic Activity of Myxoma Virus against Soft Tissue Sarcoma Is Mediated by the Overexpression of Ribonucleotide Reductase
Clinical Medicine Insights: Oncology ( IF 1.795 ) Pub Date : 2021-02-11 , DOI: 10.1177/1179554921993069
Yanghee Woo _{1,

2} , Susanne G Warner _{1,

2} , Rula Geha ₁ , Marianne M Stanford ₃ , Penelope Decarolis _{1,

4} , Masmudur M Rahman _{5,

6} , Samuel Singer ₁ , Grant McFadden _{5,

6} , Yuman Fong _{1,

2}

Affiliation

Background:

Myxoma virus (MYXV) is an oncolytic poxvirus that lacks the gene for 1 of the subunits of ribonucleotide reductase (RR), a crucial DNA synthesis and repair enzyme. The overexpression of RR has been implicated in the invasiveness of several cancers, including soft tissue sarcomas (STS). The purpose of the study was to investigate the oncolytic efficacy of MYXV in STS with different levels of RR expression.

Methods:

The oncolytic effect of recombinant MYXV was evaluated in 4 human STS cell lines, LS141 (a dedifferentiated liposarcoma), DDLS8817 (a dedifferentiated liposarcoma), RDD2213 (recurrent dedifferentiated liposarcoma), and HSSYII (a synovial sarcoma) using infectivity and cytotoxicity assays. Following the overexpression of RRM2 by cDNA transfection and silencing of RRM2 by siRRM2 in these STS cell lines, the RRM2 expression levels were analyzed by Western blot.

Results:

We observed a direct correlation between viral oncolysis and RRM2 mRNA levels (R = 0.96) in STS. Higher RRM2 expression was associated with a more robust cell kill. Silencing the RRM2 gene led to significantly greater cell survival (80%) compared with the control group (P = .003), whereas overexpression of the RRM2 increased viral oncolysis by 33% (P < .001).

Conclusions:

Our results show that the oncolytic effects of MYXV correlate directly with RR expression levels and are enhanced in STS cell lines with naturally occurring or artificially induced high expression levels of RR. Myxoma virus holds promise in the treatment of advanced soft tissue cancer, especially in tumors overexpressing RR.

中文翻译：

粘液瘤病毒对软组织肉瘤的溶瘤活性是由核糖核苷酸还原酶的过表达介导的

背景：

粘液瘤病毒 (MYXV) 是一种溶瘤痘病毒，缺乏核糖核苷酸还原酶 (RR) 的 1 个亚基的基因，RR 是一种重要的 DNA 合成和修复酶。RR 的过表达与几种癌症的侵袭性有关，包括软组织肉瘤 (STS)。该研究的目的是研究 MYXV 在具有不同 RR 表达水平的 STS 中的溶瘤功效。

方法：

重组 MYXV 的溶瘤作用在 4 个人类 STS 细胞系 LS141（去分化脂肪肉瘤）、DDLS8817（去分化脂肪肉瘤）、RDD2213（复发性去分化脂肪肉瘤）和 HSSYII（滑膜肉瘤）中使用感染性和细胞毒性试验进行了评估。在这些 STS 细胞系中通过 cDNA 转染过表达 RRM2 和通过 siRRM2 沉默 RRM2 后，通过蛋白质印迹分析 RRM2 表达水平。

结果：

我们观察到 STS 中病毒溶瘤和 RRM2 mRNA 水平 ( R = 0.96) 之间存在直接相关性。较高的 RRM2 表达与更强大的细胞杀伤相关。与对照组相比，沉默 RRM2 基因可显着提高细胞存活率 (80%) ( P = .003)，而过表达 RRM2 可使病毒溶瘤增加 33% ( P < .001)。