title: Thrombospondin-1 might be a therapeutic target to suppress RB cells by regulating the DNA double-strand breaks repair.
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.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Pei
authors.initials: P
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Na
authors.initials: N
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Nandan
authors.initials: N
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Lijun
authors.initials: L
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Jian
authors.initials: J
authors.lastname: Ge
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Keming
authors.initials: K
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, P. R. China 510060.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhuang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D053903:DNA Breaks, Double-Stranded; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011897:Random Allocation; D012175:Retinoblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D006657:Histones; D016160:Retinoblastoma Protein; D019700:Thrombospondin 1
keywords: DNA double strand breaks; Thrombospondin-1; histone deacetylation; retinoblastoma