Anlotinib inhibits synovial sarcoma by targeting GINS1: a novel downstream target oncogene in progression of synovial sarcoma
Anlotinib inhibits synovial sarcoma by targeting GINS1: a novel downstream target oncogene in progression of synovial sarcoma
复制标题
安罗替尼通过靶向 GINS1 抑制滑膜肉瘤：滑膜肉瘤进展中的一种新型下游靶癌基因
DOI：
10.1007/s12094-019-02090-2
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发表时间：
2019-12-01
影响因子：
3.4
通讯作者：
Shen, Z.
中科院分区：
文献类型：
--
作者：
Tang, L.;Yu, W.;Shen, Z.
滑膜肉瘤是一种侵袭性软组织肉瘤，对放化疗耐药，预后差。因此，迫切需要新的SS治疗策略。安洛替尼是一种新的口服酪氨酸激酶抑制剂，主要用于抑制血管生成和血管生成的多靶点。本研究旨在研究安洛替尼对晚期难治性滑膜肉瘤患者的抗肿瘤作用及其可能机制。应用基因芯片技术分析安洛替尼治疗滑膜肉瘤的下游靶点。细胞增殖和凋亡分析评估候选下游基因缺失对滑膜肉瘤细胞的影响。结果Anlotinib可显著抑制PDTX模型和细胞系中滑膜肉瘤的增殖。此外，通过基因芯片分析，GINS1(也称为PSF1，SLD Five 1的合作伙伴)，而不是其他传统的基因靶点，被证明是Anlotinib抗滑膜肉瘤作用的重要靶点。GINS1在滑膜肉瘤组织中的表达明显升高，且与预后不良有关。在体外，下调GINS1的表达可显著抑制细胞增殖，促进细胞凋亡。同时，通过基因芯片检测，确定CITED2、Egr1、SGK1和SPP1为GINS1的下游靶点。结论Anlotinib可能通过一种新的下游GINS1调控网络抑制SS的增殖，该网络在SS的增殖中起重要作用，并证明靶向GINS1调控的信号通路可能是一种潜在的SS管理策略。
BackgroundSynovial sarcoma (SS) is an aggressive soft-tissue sarcoma with a poor prognosis owing to its resistance to radiation and chemotherapy. Thus, novel therapeutic strategies for SS are urgently required. Anlotinib, a new oral tyrosine kinase inhibitor, is designed to primarily inhibit multi-targets in vasculogenesis and angiogenesis. This study was designed to characterize its antitumor efficacy and possible mechanism in patients with advanced refractory synovial sarcoma.MethodsAnlotinib’s antitumor effect was evaluated in vivo and vitro. Downstream targets of anlotinib in treating synovial sarcoma were analyzed through microarray assay. Cell proliferation and apoptosis analyses were performed to evaluate the impact of candidate downstream gene depletion in synovial sarcoma cells. Microarray assay were carried out to investigate potential signal network related with candidate downstream gene.ResultsAnlotinib significantly suppresses synovial sarcoma proliferation in PDTX model and cell lines. Additionally, GINS1 (also named as PSF1, Partner of SLD Five 1), rather than other conventional gene target, was demonstrated to be a vital target of anlotinib’s antitumor effect in synovial sarcoma through microarray assay. Expression of GINS1 was remarkably higher in synovial sarcoma tumor samples and related with poor outcome. Knockdown of GINS1 expression could remarkably inhibit proliferation and promote apoptosis in vitro. Meanwhile, through microarray assay, CITED2, EGR1, SGK1 and SPP1 were identified and further validated by qPCR/WB as downstream targets of GINS1.ConclusionAnlotinib might suppress proliferation of SS through a novel downstream GINS1-regulated network which plays a vital function in SS proliferation and also demonstrated that targeting the GINS1-regulated signal pathway could be a potential strategy for management of SS.