Oncotarget

Research Papers:

Thrombospondin-1 might be a therapeutic target to suppress RB cells by regulating the DNA double-strand breaks repair

Pei Chen, Na Yu, Zhang Zhang, Ping Zhang, Ying Yang, Nandan Wu, Lijun Xu, Jing Zhang, Jian Ge, Keming Yu and Jing Zhuang _

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Oncotarget. 2016; 7:6105-6120. https://doi.org/10.18632/oncotarget.6835

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Abstract

Pei Chen1,*, Na Yu1,*, Zhang Zhang1, Ping Zhang1, Ying Yang1, Nandan Wu1, Lijun Xu1, Jing Zhang1, Jian Ge1, Keming Yu1, Jing Zhuang1

1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060

*These authors have contributed equally to this work

Correspondence to:

Jing Zhuang, e-mail: zhuangj@mail.sysu.edu.cn

Keywords: DNA double strand breaks, histone deacetylation, retinoblastoma, Thrombospondin-1

Received: June 08, 2015    Accepted: December 29, 2015    Published: January 07, 2016

ABSTRACT

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.


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