Thrombospondin-1 might be a therapeutic target to suppress RB cells by regulating the DNA double-strand breaks repair.
Thrombospondin-1 might be a therapeutic target to suppress RB cells by regulating the DNA double-strand breaks repair.
复制标题
Thrombospondin-1 可能是通过调节 DNA 双链断裂修复来抑制 RB 细胞的治疗靶点
DOI：
10.18632/oncotarget.6835
复制
发表时间：
2016-02-02
期刊：
影响因子：
--
通讯作者：
Zhuang J
中科院分区：
文献类型：
--
作者：
Chen P;Yu N;Zhang Z;Zhang P;Yang Y;Wu N;Xu L;Zhang J;Ge J;Yu K;Zhuang J
视网膜母细胞瘤（RB）起源于视网膜，其生长通常发生在视网膜下并向玻璃体方向发展。理想的治疗应以抑制肿瘤和保护神经细胞为目标，延长患者的寿命和生活质量。先前的研究表明，血小板反应蛋白-1 （TSP-1）与神经发生、新生血管形成和肿瘤发生有关。然而，目前TSP-1在视网膜母细胞瘤中的生物活性尚未明确。在此，我们证明了TSP-1在RB细胞系和临床肿瘤样本中被沉默。HDAC抑制剂Trichostatin A （TSA）可显著上调RB细胞、WERI-Rb1细胞和Y79细胞中TSP-1的转录水平。此外，我们发现人重组TSP-1 （hTSP-1）在体外和体内均能显著抑制RB细胞的细胞活力。有趣的是，hTSP-1可以显著诱导RB细胞中DNA双链断裂（DSBs）的原位标记γ-H2AX的表达。hTSP-1可显著抑制WERI-Rb1细胞的DNA NHEJ通路。Rb1突变可能参与了htsp -1介导的WERI-Rb1细胞中γ-H2AX的增加。在神经元和视网膜母细胞瘤细胞共培养系统中，hTSP-1可以抑制RB细胞，同时促进视网膜神经细胞的存活。因此，TSP-1可能成为视网膜母细胞瘤的治疗靶点。
Retinoblastoma (RB) arises from the retina, and its growth usually occurs under the retina and toward the vitreous. Ideal therapy should aim to inhibit the tumor and protect neural cells, increasing the patient's life span and quality of life. Previous studies have demonstrated that Thrombospondin-1 (TSP-1) is associated with neurogenesis, neovascularization and tumorigenesis. However, at present, the bioactivity of TSP-1 in retinoblastoma has not been defined. Herein, we demonstrated that TSP-1 was silenced in RB cell lines and clinical tumor samples. HDAC inhibitor, Trichostatin A (TSA), could notably transcriptionally up-regulate TSP-1 in RB cells, WERI-Rb1 cells and Y79 cells. Moreover, we found human recombinant TSP-1 (hTSP-1) could significantly inhibit the cell viability of RB cells both in vitro and in vivo. Interestingly, hTSP-1 could significantly induce the expression of γ-H2AX, a well-characterized in situ marker of DNA double-strand breaks (DSBs) in RB cells. The DNA NHEJ pathway in WERI-Rb1 cells could be significantly inhibited by hTSP-1. A mutation in Rb1 might be involved in the hTSP-1-medicated γ-H2AX increasing in WERI-Rb1 cells. Furthermore, hTSP-1 could inhibit RB cells while promoting retinal neurocyte survival in the neuronal and retinoblastoma cell co-culture system. As such, TSP-1 may become a therapeutic target for treatment of retinoblastoma.