Pre-mRNA processing factor 19 functions in DNA damage repair and radioresistance by modulating cyclin D1 in hepatocellular carcinoma.
Pre-mRNA processing factor 19 functions in DNA damage repair and radioresistance by modulating cyclin D1 in hepatocellular carcinoma.
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DOI：
10.1016/j.omtn.2021.12.002
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发表时间：
2022-03-08
期刊：
影响因子：
--
通讯作者：
Shen XZ
中科院分区：
文献类型：
--
作者：
Yu XN;Zhang GC;Liu HN;Zhu JM;Liu TT;Song GQ;Dong L;Yin J;Shen XZ
前信使核糖核酸加工因子19(PRP19)在肝细胞癌中升高，但对其在肝细胞癌DNA损伤修复中的作用知之甚少。在本研究中，对肿瘤基因组图谱数据和我们的电离辐射(IR)治疗后的肿瘤模型的分析表明，PRP19的表达增加与DNA损伤修复呈正相关。质粒诱导的PRP19表达增加导致IR后细胞凋亡和双链断裂(DSB)减少，细胞存活率增加。小干扰RNA导致PRP19表达缺失，导致细胞凋亡和双链断裂积聚，细胞存活率下降。从机制上讲，PRP19对肝细胞癌DNA损伤修复的影响是通过调控细胞周期蛋白D1的表达实现的。PRP19通过调控真核细胞起始因子4E来调控细胞周期蛋白D1的翻译。PRP19通过与WD40结构域相互作用影响细胞周期蛋白D1的DNA损伤修复能力。PRP19和Cyclin D1联合检测较单项指标更能预测患者的预后。综上所述，这些结果表明PRP19通过调节细胞周期蛋白D1的表达和功能来促进DNA损伤修复，从而促进了肝癌的放射抵抗。肝细胞癌组织中PRP19的高表达与DNA损伤修复呈正相关。PRP19通过调节细胞周期蛋白D1的表达和功能，促进DNA损伤修复，从而促进细胞对放射治疗的抵抗。因此，PRP19可能成为提高肝癌放疗敏感性的一个新的治疗靶点。
Pre-mRNA processing factor 19 (PRP19) is elevated in hepatocellular carcinoma (HCC); however, little is known about its function in DNA damage repair in HCC. In this study, analysis of The Cancer Genome Atlas data and our tumor models after ionizing radiation (IR) treatment indicated that increased expression of PRP19 was positively correlated with DNA damage repair. Gain of PRP19 expression induced by plasmids resulted in decreases in apoptosis and double-strand breaks (DSBs), and an increase in cell survival after IR. Loss of PRP19 expression induced by small interfering RNAs resulted in the accumulation of apoptosis and DSBs, and a decrease in cell survival. Mechanistically, the effect of PRP19 on DNA damage repair was mediated by the modulation of cyclin D1 expression in HCC. PRP19 controlled the translation of cyclin D1 by modulating eukaryotic initiation factor 4E. PRP19 affected the DNA damage repair ability of cyclin D1 by interacting with the WD40 domain. The combination of PRP19 and cyclin D1 was more valuable than each single marker for predicting the prognosis of patients. Taken together, the present results demonstrate that PRP19 promotes DNA damage repair by modulating cyclin D1 expression and function, thereby contributing to the radioresistance in HCC. Increased expression of PRP19 was positively correlated with DNA damage repair in HCC. PRP19 promoted DNA damage repair by modulating cyclin D1 expression and function, thereby contributing to the resistance to radiotherapy. Therefore, PRP19 could be a novel therapeutic target to improve HCC sensitivity to radiotherapy.
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