Reduced Tumorigenicity of Mouse ES Cells and the Augmented Anti-Tumor Therapeutic Effects under Parg Deficiency
Reduced Tumorigenicity of Mouse ES Cells and the Augmented Anti-Tumor Therapeutic Effects under Parg Deficiency
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DOI：
10.3390/cancers12041056
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发表时间：
2020-04-01
期刊：
影响因子：
5.2
通讯作者：
Masutani, Mitsuko
中科院分区：
文献类型：
--
作者：
Sonoda, Yuki;Sasaki, Yuka;Masutani, Mitsuko
聚ADP-核糖基化是蛋白质的翻译后修饰，聚（ADP-核糖）（PAR）聚合酶（PARP）家族蛋白质使用NAD作为底物合成PAR。聚腺苷二磷酸核糖水解酶（Poly（ADP-ribose）glycohydrolase，PARG）是降解PAR的主要酶。在这项研究中，我们研究了Parg缺陷对肿瘤发生和DNA损伤剂的治疗效果的影响，使用小鼠ES细胞来源的肿瘤模型。为了检测Parg缺陷对肿瘤发生的影响，将Parg（+/+）和Parg（-/-）ES细胞皮下注射到裸鼠中。结果表明，Parg缺陷延迟ES细胞的肿瘤发生的早期发作。所有肿瘤的表型与畸胎癌相似，显微镜下发现表明Parg基因型之间的分化谱相似。在Parg缺乏的情况下，X线照射的抗肿瘤作用增强。这些结果表明，Parg缺陷抑制肿瘤发生的早期阶段，Parg抑制，与DNA损伤剂相结合，可以有效地控制特定类型的生殖细胞肿瘤的肿瘤生长。
PolyADP-ribosylation is a post-translational modification of proteins, and poly(ADP-ribose) (PAR) polymerase (PARP) family proteins synthesize PAR using NAD as a substrate. Poly(ADP-ribose) glycohydrolase (PARG) functions as the main enzyme for the degradation of PAR. In this study, we investigated the effects of Parg deficiency on tumorigenesis and therapeutic efficacy of DNA damaging agents, using mouse ES cell-derived tumor models. To examine the effects of Parg deficiency on tumorigenesis, Parg(+/+) and Parg(-/-) ES cells were subcutaneously injected into nude mice. The results showed that Parg deficiency delays early onset of tumorigenesis from ES cells. All the tumors were phenotypically similar to teratocarcinoma and microscopic findings indicated that differentiation spectrum was similar between the Parg genotypes. The augmented anti-tumor therapeutic effects of X-irradiation were observed under Parg deficiency. These results suggest that Parg deficiency suppresses early stages of tumorigenesis and that Parg inhibition, in combination with DNA damaging agents, may efficiently control tumor growth in particular types of germ cell tumors.